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Oral Mg2+ Supplementation Reverses Age-Related Neuroendocrine and Sleep EEG Changes in Humans
Abstract
The process of normal aging is accompanied by changes in sleep-related endocrine activity. During aging, an increase in cortisol at its nadir and a decrease in renin and aldosterone concentration occur. In aged subjects, more time is spent awake and slow-wave sleep is reduced: there is a loss of sleep spindles and accordingly a loss of power in the sigma frequency range. Previous studies could show a close association between sleep architecture, especially slow-wave sleep, and activity in the glutamatergic and GABAergic system. Furthermore, recent studies could show that the natural N-methyl-D-aspartate (NMDA) antagonist and GABA(A) agonist Mg(2+) seems to play a key role in the regulation of sleep and endocrine systems such as the HPA system and renin-angiotensin-aldosterone system (RAAS). Therefore, we examined the effect of Mg(2+) in 12 elderly subjects (age range 60-80 years) on the sleep electroencephalogram (EEG) and nocturnal hormone secretion. A placebo-controlled, randomised cross-over design with two treatment intervals of 20 days duration separated by 2 weeks washout was used. Mg(2+) was administered as effervescent tablets in a creeping dose of 10 mmol and 20 mmol each for 3 days followed by 30 mmol for 14 days. At the end of each interval, a sleep EEG was recorded from 11 p.m. to 7 a.m. after one accommodation night. Blood samples were taken every 30 min between 8 p.m. and 10 p.m. and every 20 min between 10 p.m. and 7 a.m. to estimate ACTH, cortisol, renin and aldosterone plasma concentrations, and every hour for arginine-vasopressin (AVP) and angiotensin 11 (ATII) plasma concentrations. Mg(2+) led to a significant increase in slow wave sleep (16.5 +/- 20.4 min vs. 10.1 +/- 15.4 min, < or =0.05), delta power (47128.7 microV(2) +21417.7 microV(2) vs. 37862.1 microV(2) +/- 23241.7 microV(2), p < or =0.05) and sigma power (1923.0 microV(2) + 1111.3 microV(2) vs. 1541.0 microV(2) + 1134.5 microV(2), p< or =0.05 ). Renin increased (3.7 +/- 2.3 ng/ml x min vs. 2.3 +/- 1.0 ng/ml x min, p < 0.05) during the total night and aldosterone (3.6 +/- 4.7 ng/ml x min vs. 1.1 +/- 0.9 ng/ml x min, p < 0.05) in the second half of the night, whereas cortisol (8.3 +/- 2.4 pg/ml x min vs. 11.8 +/- 3.8 pg/ml x min, p < 0.01) decreased significantly and AVP by trend in the first part of the night. ACTH and ATII were not altered. Our results suggest that Mg(2+) partially reverses sleep EEG and nocturnal neuroendocrine changes occurring during aging. The similarities of the effect of Mg(2+) and that of the related electrolyte Li+ furthermore supports the possible efficacy of Mg(2+) as a mood stabilizer.
... Studies were conducted between 1999 and 2019 involving a total of 8398 participants. Among nine included studies, three were cross-sectional [14,21,22], one was a cohort study [13], and the other five datasets were RCTs [15,16,[23][24][25]. Based on the country, two were from China [13,21], two from the USA [16,24], and the others were obtained from Turkey [14], Japan [22], Argentina [24], Iran [25], and Germany [23]. ...
... Among nine included studies, three were cross-sectional [14,21,22], one was a cohort study [13], and the other five datasets were RCTs [15,16,[23][24][25]. Based on the country, two were from China [13,21], two from the USA [16,24], and the others were obtained from Turkey [14], Japan [22], Argentina [24], Iran [25], and Germany [23]. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality in four studies [14,16,21,24]. ...
... The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality in four studies [14,16,21,24]. One study used the Epworth Sleepiness Scale (ESS) [21], one examined sleep electroencephalogram (EGG) [23], and one study used the Insomnia Severity Index (ISI) questionnaire [25]. In the remaining datasets, a self-report of sleep quality or quantity was used [13,15,22]. ...
To date, no study has critically reviewed the current literature on the association between magnesium (Mg) and sleep health. Therefore, we carried out a systematic review to assess the association between Mg and sleep patterns in adults’ population through observational and interventional studies. We searched for relevant studies through PubMed (http://www.ncbi.nlm.nih.gov/pubmed), Scopus (http://www.scopus.com), and ISI Web of Science (http://www.webofscience.com) from the earliest available date until November 2021. Eligibility criteria for study selection were guided by the following components identified using the PI(E)CO (Population, Intervention (Exposure), Comparison, Outcome) framework: P (adult population), I(E) (high dietary intake or supplementation of Mg), C (low dietary intake of Mg or placebo group), and O (sleep pattern including sleep duration, sleep-onset latency, night awakenings, sleep stages, and sleep phases). The present study involved 7,582 subjects from 9 published cross-sectional, cohort, and RCT systematically reviewed the possible links between Mg and sleep quality (daytime falling asleep, sleepiness, snoring, and sleep duration) in an adult population. Observational studies suggested an association between Mg statuses and sleep quality, while the RCTs reported contradictory findings. This systematic review revealed an association between magnesium status and sleep quality (daytime falling asleep, sleepiness, snoring, and sleep duration) according to the observational studies, while the randomized clinical trials showed an uncertain association between magnesium supplementation and sleep disorders. The association between dietary magnesium and sleep patterns needs well-designed randomized clinical trials with a larger sample size and longer follow-up time (more than 12 weeks) to further clarify the relationship.
... It binds to GABA receptors and activates GABA to reduce excitability of the nervous system [6]. Also, Mg can inhibit the N-methyl-d-aspartate receptor, promoting muscle relaxation via suppression of intracellular calcium (Ca) concentration in the muscle cell [7][8][9][10]. Additionally, it has been shown in rats that Mg deficiency resulted in a decrease in the concentration of plasma melatonin, a sleep-promoting hormone [11]. ...
... Additionally, it has been shown in rats that Mg deficiency resulted in a decrease in the concentration of plasma melatonin, a sleep-promoting hormone [11]. Moreover, studies have shown that Mg supplementation can decrease the concentration of serum cortisol, a stress hormone, [10,12] resulting in calming the central nervous system [13] and potentially better sleep. ...
... Although the association between Mg and sleep quality is biologically plausible and supported by previous animal and human research, [10,33,34] the association was only borderline significant in our study. One explanation is that the measurement of sleep quality, which was assessed by one question asking participants to rate their sleep quality in the past 30 days from 1 to 5. ...
Study Objectives
As an antagonist of calcium (Ca), magnesium (Mg) has been implicated in the regulation of sleep. We aimed to examine the longitudinal associations of Mg intake and Ca-to-Mg intake ratio (Ca:Mg) with sleep quality and duration.
Methods
The study sample consisted of 3,964 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Dietary and supplementary intake of Mg were obtained using the CARDIA Dietary History at baseline (1985–1986), exam years 7 and 20. Self-reported sleep outcomes were measured at years 15 and 20. Sleep quality was rating from 1 (very good) to 5 (very bad). We categorized sleep duration to <7, 7–9, and >9 h. Generalized estimating equation was used to examine the associations of interest as repeated measures at the two time points.
Results
After adjustment for potential confounders, Mg intake was borderline associated with better sleep quality [highest quartile (Q4) vs. intake quartile (Q1): odds ratio (OR) = 1.23; 95% CI = 0.999, 1.50, ptrend = 0.051]. Participants in Q4 were also less likely to have short sleep (<7 h) compared to those in Q1 (OR = 0.64; 95% CI = 0.51, 0.81, ptrend = 0.012). The observed association with short sleep persisted among participants without depressive disorders (Q4 vs. Q1: OR = 0.64; 95% CI = 0.49, 0.82, ptrend < 0.001), but not among individuals with depressive disorder. Ca:Mg was not associated with either outcomes, regardless of depression status.
Conclusions
Mg intake was associated with both sleep outcomes in this longitudinal analysis. Randomized controlled trials with objective measures of sleep are warranted to establish the potential causal inference.
... It binds to GABA receptors and activates GABA to reduce excitability of the nervous system [6]. Also, Mg can inhibit the N-methyl-d-aspartate receptor, promoting muscle relaxation via suppression of intracellular calcium (Ca) concentration in the muscle cell [7][8][9][10]. Additionally, it has been shown in rats that Mg deficiency resulted in a decrease in the concentration of plasma melatonin, a sleep-promoting hormone [11]. ...
... Additionally, it has been shown in rats that Mg deficiency resulted in a decrease in the concentration of plasma melatonin, a sleep-promoting hormone [11]. Moreover, studies have shown that Mg supplementation can decrease the concentration of serum cortisol, a stress hormone, [10,12] resulting in calming the central nervous system [13] and potentially better sleep. ...
... Although the association between Mg and sleep quality is biologically plausible and supported by previous animal and human research, [10,33,34] the association was only borderline significant in our study. One explanation is that the measurement of sleep quality, which was assessed by one question asking participants to rate their sleep quality in the past 30 days from 1 to 5. ...
Objectives
As an antagonist of calcium (Ca), magnesium (Mg) has been hypothesized to improve individuals’ sleep disturbances, a common health problem, through regulating the glutamatergic and GABAergic systems. The objectives of this study were to examine the longitudinal associations of Mg intake and Ca-to-Mg intake ratio with sleep quality and duration.
Methods
A total of 5115 American young adults, aged 18–30 years, were enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Dietary information, including intakes of Mg and other nutrients, was obtained using the CARDIA dietary history at baseline (1985–86), year 7 (1992–93), and year 20 (2005–06). Sleep measures, including self-reported sleep quality and sleep duration, were collected at year 15 (2000–01) and year 20. Sleep quality was assessed on a scale of 1 (very good) to 5 (very bad), whereas sleep duration was grouped into three categories: <7 hours, 7–9 hours, and >9 hours. Generalized estimating equation (GEE) was used to examine the associations of interest.
Results
After adjustment for potential demographical, behavioral, and nutritional confounders, Mg intake was associated with better sleep quality [highest intake quartile (Q4) vs. lowest intake quartile (Q1): odds ratio (OR) = 1.23; 95% CI = 1.00, 1.50, P for trend = 0.052]. Participants in Q4 were also less likely to have short sleep (<7 hours) compared to those in Q1 (OR = 0.64; 95% CI = 0.51, 0.81, P for trend = 0.012). The observed association with short sleep persisted among participants without depressive disorders (Q4 vs. Q1: OR = 0.64; 95% CI = 0.49, 0.82, P for trend <0.001), but not among individuals with depressive disorder. Ca-to-Mg intake ratio was not associated with either sleep quality or sleep duration regardless of depression status.
Conclusions
Mg intake was associated with sleep quality and duration in this longitudinal analysis. Randomized controlled trials with objective measures of sleep are warranted to establish the potential causal inference.
Funding Sources
National Institutes of Health (NIH).
... Two validated sleep questionnaires were reported at baseline for insomnia diagnoses as well as follow-up outcomes: the Insomnia Severity Index (ISI) [24] and the Pittsburgh Sleep Quality Index (PSQI) [26]. One study [25] employed sleep electroencephalogram (EEG) to measure insomnia and another study had participants keep a detailed sleep diary [24]. ...
... No study reported all elements required to make judgements in all risk of bias domains. While all studies were "double-blind" RCTs, zero studies reported methods of randomization sequence, allocation concealment or blinding; this placed all studies at some concern for bias, but Held (2002) was deemed higher risk for failing to report baseline characteristics [25]. Nielsen (2010) was deemed high risk for selective reporting because there was no analysis plan in the methods to explain reporting an effect of treatment on only one PSQI sub-score (out of seven) with an arbitrary cut off of ≤1 or > 1 [26]. ...
... No study reported all elements required to make judgements in all risk of bias domains. While all studies were "double-blind" RCTs, zero studies reported methods of randomization sequence, allocation concealment or blinding; this placed all studies at some concern for bias, but Held (2002) was deemed higher risk for failing to report baseline characteristics [25]. Nielsen (2010) was deemed high risk for selective reporting because there was no analysis plan in the methods to explain reporting an effect of treatment on only one PSQI sub-score (out of seven) with an arbitrary cut off of ≤1 or > 1 [26]. ...
Background
Magnesium supplementation is often purported to improve sleep; however, as both an over-the-counter sleep aid and a complementary and alternative medicine, there is limited evidence to support this assertion. The aim was to assess the effectiveness and safety of magnesium supplementation for older adults with insomnia.
Methods
A search was conducted in MEDLINE, EMBASE, Allied and Complementary Medicine, clinicaltrials.gov and two grey literature databases comparing magnesium supplementation to placebo or no treatment. Outcomes were sleep quality, quantity, and adverse events. Risk of bias and quality of evidence assessments were carried out using the RoB 2.0 and Grading of Recommendations Assessment, Development and Evaluation (GRADE) approaches. Data was pooled and treatment effects were quantified using mean differences. For remaining outcomes, a modified effects direction plot was used for data synthesis.
Results
Three randomized control trials (RCT) were identified comparing oral magnesium to placebo in 151 older adults in three countries. Pooled analysis showed that post-intervention sleep onset latency time was 17.36 min less after magnesium supplementation compared to placebo (95% CI − 27.27 to − 7.44, p = 0.0006). Total sleep time improved by 16.06 min in the magnesium supplementation group but was statistically insignificant. All trials were at moderate-to-high risk of bias and outcomes were supported by low to very low quality of evidence.
Conclusion
This review confirms that the quality of literature is substandard for physicians to make well-informed recommendations on usage of oral magnesium for older adults with insomnia. However, given that oral magnesium is very cheap and widely available, RCT evidence may support oral magnesium supplements (less than 1 g quantities given up to three times a day) for insomnia symptoms.
... No study reported all elements required to make judgements in all risk of bias domains. While all studies were "double-blind" RCTs, zero studies reported methods of randomization sequence, allocation concealment or blinding; this placed all studies at some concern for bias, but Held (2002) was deemed higher risk for failing to report baseline characteristics (23). Nielsen (2010) was deemed high risk for selective reporting because there was no analysis plan in the methods to explain reporting an effect of treatment on only one PSQI sub-score (out of seven) with an arbitrary cut off of ≤1 or >1 (22). ...
... No study reported all elements required to make judgements in all risk of bias domains. While all studies were "double-blind" RCTs, zero studies reported methods of randomization sequence, allocation concealment or blinding; this placed all studies at some concern for bias, but Held (2002) was deemed higher risk for failing to report baseline characteristics (23). Nielsen (2010) was deemed high risk for selective reporting because there was no analysis plan in the methods to explain reporting an effect of treatment on only one PSQI sub-score (out of seven) with an arbitrary cut off of ≤1 or >1 (22). ...
... Nielsen (2010) was deemed high risk for selective reporting because there was no analysis plan in the methods to explain reporting an effect of treatment on only one PSQI sub-score (out of seven) with an arbitrary cut off of ≤1 or >1 (22). Overall, Figure 3 shows that two studies were assessed to be of high risk of bias (Held, 2002;Nielsen, 2010) and one was at some risk of bias (Abbasi, 2012). ...
Background: Magnesium supplementation is often purported to improve sleep; however, as both an over-the-counter sleep aid and a complementary and alternative medicine, there is limited evidence to support this assertion. The aim was to assess the effectiveness and safety of magnesium supplementation for older adults with insomnia.
Methods: A search was conducted in three databases comparing magnesium supplementation to placebo or no treatment. Outcomes were sleep quality, quantity, and adverse events. Risk of bias and quality of evidence assessments were carried out using the RoB 2.0 and Grading of Recommendations Assessment, Development and Evaluation (GRADE) approaches. Data was pooled and treatment effects were quantified using mean differences. For remaining outcomes, a modified effects direction plot was used for data synthesis.
Results: Three trials were identified comparing oral magnesium to placebo in 151 older adults in three countries. Pooled analysis showed that post-intervention sleep onset latency time was 17.36 minutes less after magnesium supplementation compared to placebo (95% CI -27.27 to -7.44, p=0.0006). Total sleep time improved by 16.06 min in the magnesium supplementation group but was statistically insignificant. All trials were at moderate-to-high risk of bias and outcomes were supported by low to very low quality of evidence.
Conclusion: This review confirms that the quality of literature is substandard for physicians to make well-informed recommendations on usage of oral magnesium for older adults with insomnia. However, given that oral magnesium is very cheap and widely available, there is weak evidence supporting improved sleep parameters after magnesium supplementation for insomnia symptoms.
... Besides the usual methods of treating sleep disorders, including medicinal and non-medicinal methods for which there are weak evidences for their positive impact and that they produce significant side effects for patient [18], some studies have evaluated the impact of magnesium supplementation on insomnia and have reported positive results [19,20]. Evaluation of various studies shows that despite the important physiologic role of magnesium and its beneficial effects, the dietary intake of magnesium is inadequate in different societies [21] and some population groups like elderly and low educated people have low magnesium intake [22]. ...
... Regarding to Held et al. study [19], sample size was estimated to be 23 persons in each group. Insomnia severity index test was taken from the elders who referred to Culture Houses of Tehran's 1, 10, and 14 regions with insomnia complaint (as self-report). ...
... Held et al. also, in a study which dealt with magnesium supplementation in 12 healthy persons could not recognize a significant difference between two groups, despite detection of serum magnesium tendency toward increase in the supplementation group [19]. ...
Background: Strategies for weight reduction often promote lifestyle changes like
encouraging participation in physical activity. Also there is some evidence suggesting an
association between insomnia and physical activity level and probable beneficial effect of
magnesium supplementation on insomnia. The objective of this study was to determine the
effect of magnesium supplementation on physical activity level in insomniac elderly
subjects.
Materials and Methods: A double blind randomized clinical trial was conducted in 46
overweight or obese subjects, randomly allocated into the magnesium or the placebo group
and received 500 mg magnesium or placebo daily for 8 weeks. Questionnaires of insomnia
severity index (ISI), physical activity and sleep-log were completed and serum magnesium
measured at baseline and after the intervention period. Anthropometric confounding
factors, daily intake of magnesium, calcium, potassium, caffeine, calorie form
carbohydrates, fat, protein and total calorie intake, were obtained using 24-hrs recall for 3-
days. Statistical analyses were performed using SPSS-19 software.
Results: No significant differences were observed in assessed variables between the two
groups at the baseline. According to our research magnesium supplementation
significantly increased sleep indices and physical activity level, also resulted in
significantly decrease of total calorie intake in magnesium group. Although serum
magnesium concentration and weight did not show any differences.
Conclusion: In the present study magnesium supplementation resulted in improvement of
sleep indices and physical activity level in elderly subjects. Although according to our
short term intervention no significant beneficial effect was observed on subject`s weight.
... The regulation of potassium homeostasis has a wide overlap with that of magnesium, as both minerals are excreted via betaadrenergic (Whyte et al., 1987) and aldosterone-related (Horton and Biglieri, 1962;Lemann et al., 1970;Charlton and Armstrong, 1989) mechanism. Similar to potassium, magnesium increases the release of aldosterone from the adrenal cortex (Held et al., 2002), but magnesium leads also to an increase in renin release without a clear effect on angiotensin (Held et al., 2002). These and animal data suggest that magnesium has ATII antagonistic properties (Ichihara et al., 1993;Kemp et al., 1993;Held et al., 2002;Murck, 2002). ...
... The regulation of potassium homeostasis has a wide overlap with that of magnesium, as both minerals are excreted via betaadrenergic (Whyte et al., 1987) and aldosterone-related (Horton and Biglieri, 1962;Lemann et al., 1970;Charlton and Armstrong, 1989) mechanism. Similar to potassium, magnesium increases the release of aldosterone from the adrenal cortex (Held et al., 2002), but magnesium leads also to an increase in renin release without a clear effect on angiotensin (Held et al., 2002). These and animal data suggest that magnesium has ATII antagonistic properties (Ichihara et al., 1993;Kemp et al., 1993;Held et al., 2002;Murck, 2002). ...
... Similar to potassium, magnesium increases the release of aldosterone from the adrenal cortex (Held et al., 2002), but magnesium leads also to an increase in renin release without a clear effect on angiotensin (Held et al., 2002). These and animal data suggest that magnesium has ATII antagonistic properties (Ichihara et al., 1993;Kemp et al., 1993;Held et al., 2002;Murck, 2002). Possibly due to this effect magnesium depletion leads to an increase in aldosterone secretion in an animal model, which leads to anxiety-related behavior (Franklin et al., 2012a). ...
Aldosterone's primary role is to maintain sodium homeostasis as regulated by the renin–angiotensin–aldosterone system. Besides angiotensin and ACTH, potassium is a major contributor for the release of aldosterone. It is also a stress hormone, which is triggered not only by ACTH (like cortisol/corticosterone), but is in addition stimulated via the sympathetic nervous system via beta-adrenergic pathways and the renin–angiotensin system. Activation of the mineralocorticoid receptor (MR) by aldosterone leads to an increase in blood pressure and sodium retention and has proinflammatory activity, thus preparing the organism for a fight or flight reaction. Further, social isolation, which is a risk factor for anxiety and depression, is related to an increase in aldosterone. A close interaction with oxytocin regulation appears to exist. Classical hippocampal MR are to a large degree occupied by cortisol/corticosterone most of the time and aldosterone has a limited effect. MRs in specific brain areas, primarily the nucleus of the solitary tract (NTS), are sensitive to aldosterone. Reciprocal connections exist between the NTS and behaviorally relevant areas, including the central nucleus of the amygdala, the paraventricular nucleus, the nucleus accumbens, the anterior cingulate cortex, and the insula. An aldosterone-sensitive functional system emerges, which is involved in the control of vegetative regulation, like that of blood pressure, heart rate, slow wave sleep, salt appetite, but also interoception and emotionality. This system is modified by both genetic and epigenetic levels. MR activity-related biomarkers can be utilized to further characterize specific groups of patients, which are treatment refractory to standard antidepressants and who may require a manipulation of the MR activity in order to show clinical improvement.
... Magnesium was administered to the patients in 10 mmol doses and 20 mmol doses each for 3 days, and this was followed by 30 mmol doses for 2 weeks (i.e., 14 days). It was observed that wakefulness was reduced; however, this finding did not reach a level of significance [39]. Moreover, a recent crossover randomized double-blind placebo-controlled trial that included a total of 42 participants (average age 61.6 years) observed no effect on sleep disorders caused by nocturnal leg cramps when oral magnesium citrate was administered twice a day for one month [40]. ...
... In a study similar to the present, Lai et al. showed that there was a negative correlation between serum magnesium levels and EDS in peritoneal dialysis patients; and in multivariate regression analysis, urinary magnesium was an independent predictor of EDS [41]. Previous evidence suggests that magnesium regulates sleep; because it acts as an NMDA and a GABA agonist, sleep architecture is closely associated with the glutamatergic and GABAergic system [20,39]. Indeed, the use of glutamatergic and GABAergic system modulators in the treatment of EDS has been of recent interest [42]. ...
Citation: Tunc, M.; Soysal, P.; Pasin, O.; Smith, L.; Rahmati, M.; Yigitalp, V.; Sahin, S.; Dramé, M. Hypomagnesemia Is Associated with Excessive Daytime Sleepiness, but Not Insomnia, in Older Adults. Nutrients 2023, 15, 2467. Abstract: The aim of this study was to investigate associations between serum magnesium levels with insomnia and excessive daytime sleepiness (EDS) in older adults. A total of 938 older outpatients were included in the study. Hypomagnesemia was defined as serum magnesium concentration below <1.6 mg/dL. Patients were divided into two groups: hypomagnesemia and normomagnesia (1.6-2.6 mg/dL). The Epworth Sleepiness Scale was implemented and scores of ≥11 points were categorized as EDS. The Insomnia Severity Index was implemented and scores of ≥8 indicated insomnia. The mean age was 81.1 ± 7.6 years. While the presence of EDS, hypertension, diabetes mellitus, and coronary artery disease were more common in the hypomagnesemia group than the normomagnesia group, Parkinson's disease was less common (p < 0.05). Hemoglobin and HDL cholesterol were lower, whereas HbA1c, triglyceride, and number of drugs used were higher in the hypomagnesemia group compared to the normomagnesia group (p < 0.05). In both univariate analysis and multivariate analysis adjusted for gender, age and all confounders, there were significant associations between hypomagnesemia and EDS [odds ratio (OR):1.7; 95% confidence interval (CI): 1.6-2.6, and OR: 1.9; 95%CI: 1.2-3.3, respectively (p < 0.05)]. There was no significant relationship between hypomagnesemia and insomnia (p > 0.05). The present study identified an association between hypomagnesemia and EDS in older adults. Therefore, it may be prudent to consider hypomagnesemia when evaluating older adults with EDS and vice versa.
... Among other age-related changes unrelated to the genome, loss of proteostasis and nutrient homeostasis and the appearance of waste products (ROS or lipofuscin) have also been pointed out [85]. Deregulation of nutrient perception due to neuroendocrine changes has been reported [90], and supplementation with oral magnesium can reverse such age-related neuroendocrine changes in humans [91]. The accumulation of free radicals characteristic of aging can also be reduced by magnesium supplementation, as the cation reduces the presence of inflammation and ROS [92]. ...
... This is due to the aforementioned nutrient sensing, in which the effect of the somatotropic axis of growth hormone (GH) and insulin growth factor 1 is reduced [127]. Remarkably, magnesium has been reported to have an effect on GH [128] and its supplementation reverses neuro-endocrine changes in humans [91]. ...
Within the organism, the liver is the main organ responsible for metabolic homeostasis and xenobiotic transformation. In order to maintain an adequate liver weight-to-bodyweight ratio, this organ has an extraordinary regenerative capacity, able to respond to an acute insult or partial hepatectomy (PH). Maintenance of hepatic homeostasis is crucial for the proper functioning of the liver, and in this context, an adequate nutrition with macro- and micronutrient intake is mandatory. Among all known macro-minerals, magnesium has a key role in energy metabolism and in metabolic and signaling pathways that maintain liver function and physiology throughout its life span. In the present review, the cation is reported as a potential key molecule during embryogenesis, liver regeneration, and aging. The exact role of the cation during liver formation and regeneration is not fully understood due to its unclear role in the activation and inhibition of those processes, and further research in a developmental context is needed. As individuals age, they may develop hypomagnesemia, a condition that aggravates the characteristic alterations. Additionally, the risk of developing liver pathologies increases with age and hypomagnesemia may be a contributing factor. Therefore, magnesium loss must be prevented by adequate intake of magnesium-rich foods such as seeds, nuts, spinach, or rice to prevent age-related hepatic alterations and contribute to the maintenance of hepatic homeostasis. Since magnesium-rich sources include a variety of foods, a varied and balanced diet can meet both macro- and micronutrient needs.
... Modest evidence suggests that such modalities, as cognitive, psychological, or exercise interventions to lower chronic stress, may improve immune function [225]. Magnesium supplementation in older subjects has also been reported to lower nighttime GC levels [226,227]. ...
... Therefore, the means to improve sleep quality or quantity, or to entrain circadian rhythms, may be a potential means to ameliorate secondary immunological aging and age impairments in NK function. In addition to cognitive-behavioral therapy and therapeutic sleep restriction for insomnia and sleep hygiene for more general poor sleep [246], some specific interventions demonstrated to improve sleep in older persons include magnesium supplementation [226,227] and creating a peripheral temperature gradient via wearing socks in bed [247,248] or through pre-bed hot baths [249]. ...
Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer’s and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its role in infectious disease. One aspect of immunosenescence that has received less attention is age-related natural killer (NK) cell dysfunction, characterized by reduced cytokine secretion and decreased target cell cytotoxicity, accompanied by and despite an increase in NK cell numbers with age. Moreover, recent studies have revealed that NK cells are the central actors in the immunosurveillance of senescent cells, whose age-related accumulation is itself a probable contributor to the chronic sterile low-grade inflammation developed with aging (“inflammaging”). NK cell dysfunction is therefore implicated in the increasing burden of infection, malignancy, inflammatory disorders, and senescent cells with age. This review will focus on recent advances and open questions in understanding the interplay between systemic inflammation, senescence burden, and NK cell dysfunction in the context of aging. Understanding the factors driving and enforcing NK cell aging may potentially lead to therapies countering age-related diseases and underlying drivers of the biological aging process itself.
... Mg led to an increase of slow wave sleep and delta and sigma power, an increase in renin and aldosterone secretion, and a decrease in cortisol by tendency. According to the authors, data presented support "the possible efficacy of Mg as a mood stabilizer" [83]. Consistent with these data are the results of Abbasi et al. [84]: 43 adults aged 65 years of both sexes received 500 mg Mg (as the oxide) daily for 8 weeks or placebo. ...
... The individual Mg dose to achieve this might be vastly different, and physiological doses of Mg often are insufficient to reach this goal. Therefore, higher doses of Mg (often named "pharmacological doses") are needed for a significant increase in plasma Mg, for instance up to 30 mmol/day (720 mg) as described by Held et al. [83]. Many studies reporting poor therapeutic effects of oral Mg might be hampered by the fact that the chosen Mg dose was too low and treatment duration too short. ...
... Sleep deprivation may induce acid-base homeostatic imbalance (Madan and Jha 2012a). On the other hand, different ions may also influence sleep architecture (Held et al. 2002). There is a definite evidence suggesting that the two independent systems are closely linked. ...
... Hz), but does not change SWS delta power throughout the night (Murck and Steiger 1998). Later, Held et al. have reported that oral administration of magnesium significantly increased slowwave sleep as well as EEG delta and sigma power in elderly subjects (Held et al. 2002). In elderly subjects, magnesium supplement appears to improve insomnia and early morning awakening and serum melatonin concentration (Abbasi et al. 2012). ...
Several studies have suggested that physiological sleep is an indispensable part of the system. It is, however, not known what sleep does to our brain and body. Sleep helps to modulate transcription and translational processes, synaptic neurotransmission, metabolic processes, detoxification, restitution, proliferation, thermoregulation and neuro-immuno-endocrine information, stress reactions, emotional fluctuations, growth, timekeeping, and strategy for survival. In addition, evidences suggest that sleep could be involved in the maintenance of inter- and intracellular microenvironments. Sleep may modulate the homeostatic regulation of (a) acid-base balance, (b) biological buffer system, and (c) ionic/electrolytic balances. We have proposed earlier that one of the essential functions of REM sleep could be to maintain normal bodily CO2 level during sleep. The elevated bodily CO2 level during prolonged vigilant states can adversely alter the cellular ionic milieu. Therefore, it is essential that the level of CO2 must remain within physiological limits, and sleep seems to play an essential role in the maintenance of physiological CO2 level. Furthermore, sleep may also be playing an essential role in maintaining homeostatic balance of several ions such as iron, calcium, potassium, sodium, zinc, magnesium, etc. In this chapter, we discuss the role of sleep in the maintenance of ionic and acid-base balances. We have also addressed how the chronic and acute sleep loss can cause ionic imbalances leading to cellular distress. Further, we have attempted to highlight the influence of ionic homeostatic dysregulation on cognitive performances.
... Exposure to stress moderates serum (noise stress; [47]) and intracellular (exam stress; [48]) Mg levels. Magnesium supplementation has also been shown to attenuate the activity of the HPAA, including a reduction in central (ACTH; [15]) and peripheral (cortisol; [49]) endocrine responses of this system. Therefore, Mg may further influence anxiety states via the moderation of the stress response. ...
... The potential effect of Mg in attenuating psychological response to stress merits further investigation since stress is a ubiquitous feature of modern lives. The modulation of the HPA axis by Mg, which has been demonstrated to reduce central (ACTH; [15]) and peripheral (cortisol; [49]) endocrine responses, suggests that behavioural effects of stress exposure such as anxiety could be attenuated by Mg supplementation. ...
Background:
Anxiety related conditions are the most common affective disorders present in the general population with a lifetime prevalence of over 15%. Magnesium (Mg) status is associated with subjective anxiety, leading to the proposition that Mg supplementation may attenuate anxiety symptoms. This systematic review examines the available evidence for the efficacy of Mg supplementation in the alleviation of subjective measures of anxiety and stress.
Methods:
A systematic search of interventions with Mg alone or in combination (up to 5 additional ingredients) was performed in May 2016. Ovid Medline, PsychInfo, Embase, CINAHL and Cochrane databases were searched using equivalent search terms. A grey literature review of relevant sources was also undertaken.
Results:
18 studies were included in the review. All reviewed studies recruited samples based upon an existing vulnerability to anxiety: mildly anxious, premenstrual syndrome (PMS), postpartum status, and hypertension. Four/eight studies in anxious samples, four/seven studies in PMS samples, and one/two studies in hypertensive samples reported positive effects of Mg on subjective anxiety outcomes. Mg had no effect on postpartum anxiety. No study administered a validated measure of subjective stress as an outcome.
Conclusions:
Existing evidence is suggestive of a beneficial effect of Mg on subjective anxiety in anxiety vulnerable samples. However, the quality of the existing evidence is poor. Well-designed randomised controlled trials are required to further confirm the efficacy of Mg supplementation.
... Magnesium is involved in more than 300 metabolic reaction pathways including the production of melatonin, which regulates the sleep cycle [25]. Human and animal studies have implicated magnesium in the modulation of sleep [26][27][28][29][30][31]. Vitamin B6 may indirectly promote sleep quality through its role in the synthesis of a number of neurotransmitters involved in sleep regulation, including dopamine, serotonin, glutamate, γ-aminobutyric acid (GABA), and histamine [32,33]. ...
... The rationale for inclusion of magnesium and vitamin B6 in LZComplex3 is based on in vitro and animal studies suggesting they may promote sleep quality by supporting metabolic pathways involved in sleep regulation, rather than due to any direct sedative activity [26][27][28][29][30][31][32][33]. Given the current clinical evidence base for the individual components in LZComplex3, it is difficult to determine whether the primary endpoint of this study was not met because of an absence of sedative activity, unknown complex pharmacokinetic interaction between the individual active ingredients, or because of methodological factors. ...
Acute, non-clinical insomnia is not uncommon. Sufferers commonly turn to short-term use of herbal supplements to alleviate the symptoms. This placebo-controlled, double-blind study investigated the efficacy of LZComplex3 (lactium™, Zizyphus, Humulus lupulus, magnesium and vitamin B6), in otherwise healthy adults with mild insomnia. After a 7-day single-blind placebo run-in, eligible volunteers (n = 171) were randomized (1:1) to receive daily treatment for 2 weeks with LZComplex3 or placebo. Results revealed that sleep quality measured by change in Pittsburgh Sleep Quality Index (PSQI) score improved in both the LZComplex3 and placebo groups. There were no significant between group differences between baseline and endpoint on the primary outcome. The majority of secondary outcomes, which included daytime functioning and physical fatigue, mood and anxiety, cognitive performance, and stress reactivity, showed similar improvements in the LZComplex3 and placebo groups. A similar proportion of participants reported adverse events (AEs) in both groups, with two of four treatment-related AEs in the LZComplex3 group resulting in permanent discontinuation. It currently cannot be concluded that administration of LZComplex3 for 2 weeks improves sleep quality, however, a marked placebo response (despite placebo run-in) and/or short duration of treatment may have masked a potential beneficial effect on sleep quality.
... Exposure to stress moderates serum (noise stress; [47]) and intracellular (exam stress; [48]) Mg levels. Magnesium supplementation has also been shown to attenuate the activity of the HPAA, including a reduction in central (ACTH; [15]) and peripheral (cortisol; [49]) endocrine responses of this system. Therefore, Mg may further influence anxiety states via the moderation of the stress response. ...
... The potential effect of Mg in attenuating psychological response to stress merits further investigation since stress is a ubiquitous feature of modern lives. The modulation of the HPA axis by Mg, which has been demonstrated to reduce central (ACTH; [15]) and peripheral (cortisol; [49]) endocrine responses, suggests that behavioural effects of stress exposure such as anxiety could be attenuated by Mg supplementation. ...
Experimental studies of anxiety in animal models, and evidence of efficacious outcomes of magnesium (Mg) supplementation in the treatment of acute clinical affective disorders, has increased interest in Mg as a potential novel treatment for symptoms of mild/moderate subjective anxiety. This short review examines the existing evidence for the effects of Mg supplementation on subjective anxiety in humans. Additionally, evidence from three unpublished studies that examined Mg and vitamin B6 intake on subjective anxiety is summarised to supplement the existing literature.
CONCLUSIONS
The efficacy of Mg in the treatment of anxiety in the mildly anxious and those reporting premenstrual syndrome-related anxiety is suggestive of a beneficial effect of Mg intake. Further randomised controlled trials are warranted to further establish the efficacy of Mg as a novel treatment for subjective anxiety.
... Mg is an essential mineral that acts as a cofactor in over 300 enzyme systems (Schwalfenberg and Genuis 2017). Previous studies have shown that Mg is involved in the regulation of cellular timekeeping, energy balance, and sleep electroencephalogram (EEG) patterns (Feeney et al. 2016;Held et al. 2002). Mg deficiency has also been explored in various clinical conditions, including sleep disorders (Arab et al. 2023;Han et al. 2024;Serefko, Szopa, and Poleszak 2016). ...
Background
Sleep disturbances have become increasingly prevalent in modern society. Research suggests that a deficiency in magnesium (Mg) may contribute to sleep disturbances. This study aims to investigate the association between daily Mg intake and self‐reported sleep duration and sleep disorders using data from the National Health and Nutrition Examination Survey (NHANES).
Methods
The study dataset includes participants from five cycles (2009–2018) of NHANES. The associations between Mg intake and sleep duration are analyzed using weighted logistic regression.
Results
Baseline characteristics of 21,840 participants were analyzed. Mg intake was independently associated with sleep duration (OR = 1.07, 95% CI (1.01–1.14), p = 0.024). Higher quartiles of Mg intake from food were associated with normal sleep duration. However, Mg intake from food in participants with self‐reported sleep disorders did not differ from those without sleep disorders (OR = 0.96, 95% CI (0.90–1.03), p = 0.238). Among 3923 participants with Mg supplementation data, no significant differences were found between the top and bottom 50% Mg supplementary groups regarding sleep duration or disorders.
Conclusions
Dietary Mg intake is independently associated with self‐reported short sleep duration but not with self‐reported sleep disorders. Mg supplementation is not associated with either self‐reported sleep duration or sleep disorders.
... Held et al. assessed the effects of magnesium medication for 20 days on the phases of sleep in 12 older persons in a placebo-controlled randomized crossover research; however, they used different sleep assessment techniques. Their results corroborated current research findings since it was shown that taking magnesium supplements caused a considerable elevation in slow-wave (deep) sleep (20). The present research results were also supported by a study on patients with insomnia, which found that supplementing with magnesium, melatonin, and vitamin B complex for 3 months was useful in treating insomnia of any kind, independent of the underlying reason (21). ...
Objectives
Diabetes mellitus is a metabolic condition with hyperglycemia. Literature has shown a correlation between poor sleep quality and duration with an increased incidence of insomnia in diabetic individuals. The goal of this study was to determine the magnesium and potassium supplementation effect among diabetic individuals with insomnia.
Methods
A randomized controlled trial (single blind) was conducted on 320 patients with diabetes; after 2 months of follow-up, 290 patients completed the trial. The Insomnia Severity Index (ISI) was used to assess the severity and duration of insomnia, before and after the trial. Tablets containing supplements were prepared: placebo (T1), magnesium (Mg, T2), potassium (K, T3), and a combination of Mg and K (T4). Melatonin and cortisol (sleep hormones) were measured from blood (serum) using an enzyme-linked immunosorbent assay (ELISA), before and after the trial.
Results
The study included 93 (32.1%) male and 197 (67.9%) female participants. According to the analysis, there was a significant association between the treatment groups and ISI after the trial (post-trial), p = 0.0001. Analysis showed that there was significant association between pre- and post-serum cortisol levels in treatment groups 2, 3, and 4 (T2, T3, and T4) as p-values are 0.001, 0.001, and 0.001 respectively. Similar findings were observed for serum melatonin.
Conclusions
The study revealed that magnesium, potassium, and magnesium and potassium combined had a significant effect on serum cortisol and melatonin levels (sleep hormones). In addition, supplementation significantly decreased the severity of insomnia among patients with diabetes by improving sleep duration.
... Furthermore, binding to GABA receptors and activating them indirectly causes a relaxation in the activity of the central nervous system [78]. Magnesium can also decrease the serum cortisol concentration, which may contribute to improved sleep patterns [77,79]. ...
The effect of diet on sleep quality has been addressed in many studies; however, whether/how plant-based diets (PBDs) impact sleep-related parameters has not been explored in detail. This review aims to give an overview of the components of PBDs and the possible mechanisms through which PBDs may improve sleep quality. Studies have indicated that diets such as PBDs, which are typically high in fruits, vegetables, nuts, seeds, whole grains, and fiber, are associated with better sleep outcomes, including less fragmented sleep and improved sleep duration. Several mechanisms may explain how PBDs impact and/or improve sleep outcomes. Firstly, PBDs are characteristically rich in certain nutrients, such as magnesium and vitamin B6, which have been associated with improved sleep patterns. Secondly, PBDs are often lower in saturated fats and higher in fiber, which may contribute to better overall health, including sleep quality. Additionally, plant bioactive compounds like phytochemicals and antioxidants in fruits, vegetables, and herbs may have sleep-promoting effects. According to available data, PBD and Mediterranean diet elements promise to enhance sleep quality; however, it is crucial to note that diets should be customized based on each person’s needs.
... Similarly, in mice fed a magnesium-deficient diet, anxiety-like behavior was observed, along with a change in the composition of the gut microbiome [28]. Magnesium may have a therapeutic effect, as supplementation with magnesium lowered the cortisol level, a marker of stress [29]. It is not known, however, whether magnesium is effective in treating anxiety and SRB overgrowth. ...
The gut microbiota–brain axis allows for bidirectional communication between the microbes in our gastrointestinal (GI) tract and the central nervous system. Psychological stress has been known to disrupt the gut microbiome (dysbiosis) leading to anxiety-like behavior. Pathogens administered into the gut have been reported to cause anxiety. Whether commensal bacteria affect the gut–brain axis is not well understood. In this study, we examined the impact of a commensal sulfate-reducing bacteria (SRB) and its metabolite, hydrogen sulfide (H2S), on anxiety-like behavior. We found that mice gavaged with SRB had increased anxiety-like behavior as measured by the open field test. We also tested the effects of magnesium oxide (MgO) on SRB growth both in vitro and in vivo using a water avoidance stress (WAS) model. We found that MgO inhibited SRB growth and H2S production in a dose-dependent fashion. Mice that underwent psychological stress using the WAS model were observed to have an overgrowth (bloom) of SRB (Deferribacterota) and increased anxiety-like behavior. However, WAS-induced overgrowth of SRB and anxiety-like behavioral effects were attenuated in animals fed a MgO-enriched diet. These findings supported a potential MgO-reversible relationship between WAS-induced SRB blooms and anxiety-like behavior.
... 0 American Journal of Lifestyle Medicine tablets (Mg2+) at an escalating dose of 10 mmol and 20 mmol each for 3 days followed by 30 mmol daily for 14 days. 56 Of note, this review concluded that the outcomes were supported by low to very low quality of evidence. In addition, magnesium threonate has been reported to cross the blood-brain-barrier more effectively in an animal model, but this form has not been evaluated for its effects on sleep, though a clinical trial is underway. ...
Background: Healthy aging is defined as survival to advanced age while retaining autonomy in activities of daily living, high societal participation, and good quality of life. Sarcopenia, insomnia, cognitive impairment, and changes in sensation can be key hinderances to healthy aging, but nutritional supplements may abate their impact. As research advances, an updated review on their efficacy on age-related conditions is warranted. Results: Sarcopenia can be mitigated through proper protein intake, supplements like creatine, and in certain situations Branched-Chain Amino Acids and Vitamin D, in adults over 65. Melatonin supplementation has moderate evidence for improving sleep, while valerian root lacks evidence. Magnesium, tart cherry, and kiwifruits have shown promising impacts on sleep in limited articles. Magnesium, Vitamin D, and B vitamin supplementation have been shown to improve cognition in those with mild cognitive impairment and Alzheimer’s disease but require further study prior to recommendation. The Age-Related Eye Disease Study supplement combination is routinely recommended to reduce risk of progression to advance stages of age-related macular degeneration. Alpha-Lipoic Acid and Folate have been investigated for their roles in mitigating age-related hearing losses. Conclusions: Nutritional supplements and lifestyle changes may mitigate disabilities across multiple domains of age-related illnesses and promote healthy aging.
... Activation of the HPAA triggers sympathetic, neuroendocrine and behavioural responses to cope with the stressor -one of these responses is increased anxiety. Magnesium supplementation has been shown to suppress HPAA activity by reducing ACTH [16] and cortisol [38] secretion and, therefore, may have the effect of reducing the incidence of anxiety by moderating the stress response. ...
Introduction and purpose: The main aim of our study is to summarise existing knowledge and draw conclusions about the impact of magnesium deficiency on the occurrence of anxiety. Methodology: The literature available in the National Library of Medicine database at https://pubmed.ncbi.nlm.nih.gov and Google Scholar was reviewed. Articles were searched by using keywords: magnesium, deficiency, supplementation, anxiety disorders. Forty-seven research papers and meta-analyses were analysed. Description of the state of knowledge: Magnesium is an extremely important mineral in the human body involved in many physiological processes. A deficiency of this element affects the whole body and can cause mental disorders - including anxiety disorders. There are many theories showing a link between magnesium and anxiety disorders in both humans and animals. Magnesium has been shown to influence the function of neurotransmitters affecting the experience of anxiety. Supplementation in people with hypomagnesaemia has been proven to improve their health and well-being. However, it should be noted that supplements on the market vary in the bioavailability of the mineral, and the frequency of intake and dosage also affect the bioavailability of magnesium. Conclusions: It is important to ensure adequate levels of magnesium in the diet, given its impact on the proper functioning of the human body (including the nervous system) and the fact that most people consume insufficient amounts of this macronutrient. Evidence of a link between magnesium levels and anxiety has led to increased interest in the potential efficacy of magnesium supplementation to alleviate anxiety symptoms.
... Se-yeast was more efficacious than selenite in preserving Se status during stress (Rider et al. 2009). Deficiencies in magnesium, in particular, cause negative effects across the HPA axis (Held et al. 2002). In times of extreme stress, a calcium-to-magnesium ratio of 1:1 is recommended. ...
Cancer is the second leading cause of morbidity and mortality globally because it is usually detected at advanced stages. If detected early, deaths by cancer can be reduced and survival can be prolonged. Different types of cells possess unique molecular signatures and characteristics in particular conditions, which can be measured objectively and serve as the biomarker for that condition. Various biomolecules present in tissues, blood, and other body fluids may indicate the presence of cancer. Cancer biomarkers are useful tools for risk assessment, early detection, diagnosis, prognosis, and recurrence of cancer. Identification of reliable biomarkers can bring a deep understanding of carcinogenesis and help guide the clinicians in early detection and treatment of cancer. In the field of oncology, biomarker discovery has revolutionized the process of cancer treatment by focusing on the actionable targets in a cancer patient.KeywordsCancer, biomarkerEarly detectionDiagnosisPrecision medicineOncology
... Molecular mechanisms via which Mg contributes to sleep remain unclear. One possibility is that Mg may help increase N-methyl-D-aspartate receptor function, which in turn regulates sleep [52]. Furthermore, Mg may also act as a serotonin N-acetyltransferase, promoting transformations of serotonin to N-acetylserotonin and participating in melatonin synthesis [53]. ...
Previous studies have related single essential metal elements (EMEs) to sleep quality among older adults, however, the association of the EME mixture with sleep quality remained poorly understood. This study aimed to investigate the relationships between single EMEs and the EME mixture and sleep quality in older adults living in Chinese communities. This study consisted of 3957 older adults aged 60 years or over. Urinary concentrations of cobalt (Co), vanadium (V), selenium (Se), molybdenum (Mo), strontium (Sr), calcium (Ca), and magnesium (Mg) were detected using inductively coupled plasma mass spectrometry. Sleep quality was evaluated using Pittsburgh Sleep Quality Index (PSQI). The associations of single EMEs and EME mixture with sleep quality were assessed using logistic regression and Bayesian kernel machine regression (BKMR) models, respectively. Adjusted single-element logistic regression models showed that Mo (OR = 0.927, 95%CI:0.867–0.990), Sr (OR = 0.927, 95%CI:0.864–0.994), and Mg (OR = 0.934, 95%CI:0.873–0.997) were negatively related to poor sleep quality. BKMR models exhibited similar results. Also, higher levels of the EME mixture in urine were inversely related to the odds of poor sleep quality after adjustment for covariates, and Mo had the largest conditional posterior inclusion probability (condPIP) value in the mixture. Mo, Sr, and Mg were negatively related to poor sleep quality, separately and as the mixture. The EME mixture in urine was associated with decreased odds of poor sleep quality in older adults, and Mo was the greatest contributor within the mixture. Additional cohort research is warranted to clarify the relationship of multiple EMEs with sleep quality.
... The nutritional regulation of sleep has been of consistent research interest for many years, most notably in athletic populations, as has been recently addressed in a number of narrative reviews and an expert consensus statement (1,10,11). Several studies have examined various nutritional ingredients with proposed sleep enhancing qualities across a range of participant groups with and without sleep disorders, inclusive of high glycemic index carbohydrates (12,13), tryptophan (14), tart cherries (15,16), glycine (17), magnesium (18), and L-theanine (19). Within these investigations, there have been numerous suggested regulatory mechanisms, with metabolomic interactions of specific neurotransmitters involved in the sleep/wake cycle, purported to enhance regulation of the circadian rhythm of sleep (20). ...
Purpose:
To test the hypothesis that a novel nutritional blend comprised of tryptophan, glycine, magnesium, tart cherry powder and L-theanine, enhances subjective and objective measures of sleep during free living conditions.
Methods:
In a randomised, repeated measures crossover and double blind deception design, participants (n = 9 male and 7 female; age: 24 ± 3 years; body mass: 69.8 ± 11.6 kg; stature: 170.8 ± 9.1 cm) completed a 3 day familiarisation period, followed by 3 day intervention and placebo trials. Subjective Pittsburgh Quality Sleep Index, Core Consensus Sleep Diary and Karolinska Sleepiness Scale survey tools, alongside objective actigraphy measures of sleep were assessed, with daily nutritional intake, activity and light exposure standardised between trials. Participants provided daily urine samples for assessment of targeted and untargeted metabolomes.
Results:
The intervention trial reduced sleep onset latency (-24 ± 25 mins; p = 0.002), increased total sleep time (22 ± 32 mins; p = 0.01) and sleep efficiency (2.4 ± 3.9 %; p = 0.03), whilst also reducing morning sleepiness (p = 0.02). Throughout the study, 75 % of participants remained blinded to sleep assessment as a primary outcome measure, with 56 % subjectively indicating improved sleep during the intervention trial. Metabolomic analysis highlighted several significantly altered metabolomes related to sleep regulation between trials, inclusive of 6-sulfatoxymelatonin, D-serine and L-glutamic acid.
Conclusions:
Data demonstrate that employing the proposed blend of novel nutritional ingredients during free living conditions reduced sleep onset latency, increased total sleep duration and increased sleep efficiency, leading to reduced perceptions of morning sleepiness. These effects may be mediated by the upregulation of key metabolites involved in the neurophysiological modulation of the sleep/wake cycle.
... mmol / l. [4] Low levels of magnesium in the body may be a result of its low intake with food, impaired absorption and its increased loss by the kidneys. [18] Emotional stress may also be the cause of magnesium loss. Magnesium deficiency can lead to seizures, weakness, hallucinations, and depression, which are reversible when the magnesium levels in the brain are balanced. ...
Magnesium is a very important macronutrient in the human body. Its main storage is bones. The correct concentration of this macronutrient within the normal range is necessary for the proper functioning of the body. Deficiency of this element negatively affects the entire body. One of the symptoms of magnesium deficiency is depression and other psychiatric disorders. The factors explaining the mechanism of magnesium's antidepressant effect are not fully understood, however, a relationship between magnesium deficiency and the pathogenesis of depression has been demonstrated. Supplementation with preparations of this element improves the condition in ill people with depression. [3][6]
... Magnesium influences activity of the hypothalamic-pituitary-adrenal axis, which instigates various responses to cope with stress demands (Murck, 2002). Magnesium also reduces central adrenocorticotrophic hormone (Murck, 2002) and peripheral (cortisol) endocrine responses (Held et al., 2002), thereby decreasing anxiety. Additionally, magnesium may help reduce presynaptic glutamate release (Papadopol & Nechifor, 2011) and glutamatergic activity that has been implicated in fear, anxiety and panic responses (Boyle et al., 2017;Clerc et al., 2013). ...
Magnesium status and vitamin B6 intake have been linked to mental health and/or quality of life (QoL). In an 8‐week Phase IV randomised controlled study in individuals with low magnesemia and severe/extremely severe stress but who were otherwise healthy, greater stress reduction was achieved with magnesium combined with vitamin B6 than with magnesium alone. Here, we present a previously unreported secondary analysis of the effect of magnesium, with and without vitamin B6, on depression, anxiety, and QoL. Adults with Depression Anxiety Stress Scales (DASS‐42) stress subscale score >18 were randomised 1:1 to magnesium+vitamin B6 combination (Magne B6®; daily dose 300mg and 30mg, respectively) or magnesium alone (Magnespasmyl®; daily dose 300mg). Outcomes included changes from baseline in DASS‐42 depression and anxiety scores, and QoL (Short Form‐36 Health Survey). DASS‐42 anxiety and depression scores significantly improved from baseline to week 8 with both treatments, particularly during the first 4 weeks. Improvement in QoL continued over 8 weeks. Participants’ perceived capacity for physical activity in daily life showed greater improvement with magnesium+vitamin B6 than magnesium alone (Week 4). In conclusion, magnesium supplementation, with or without vitamin B6, could provide a meaningful clinical benefit in daily life for individuals with stress and low magnesemia.
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... Magnesium influences activity of the hypothalamic-pituitary-adrenal axis, which instigates various responses to cope with stress demands (Murck, 2002). Magnesium also reduces central adrenocorticotrophic hormone (Murck, 2002) and peripheral (cortisol) endocrine responses (Held et al., 2002), thereby decreasing anxiety. Additionally, magnesium may help reduce presynaptic glutamate release (Papadopol & Nechifor, 2011) and glutamatergic activity that has been implicated in fear, anxiety and panic responses (Boyle et al., 2017;Clerc et al., 2013). ...
Primary findings from a recent study reported that magnesium supplementation significantly reduced stress in severely stressed subjects with low magnesemia, and additional vitamin B6 enhanced this effect. The mechanism by which combining magnesium and vitamin B6 leads to reduced stress in these subjects remains to be elucidated. This secondary analysis investigated the impact of magnesium and vitamin B6 supplementation and perceived stress on erythrocyte magnesium levels, as a marker of body magnesium status. This was a secondary analysis from an 8-week randomized controlled trial comparing oral magnesium (300 mg) and magnesium-vitamin B6 (300 mg + 30 mg) supplementation. Stress level and erythrocyte magnesium level at baseline, and change in erythrocyte magnesium and serum vitamin B6 levels at weeks 4 and 8, were analyzed. Overall, 264 subjects were randomized to treatment and had evaluable Depression Anxiety Stress Scale scores (132 in each treatment arm). At baseline, stress scores, and mean serum magnesium, erythrocyte magnesium, and serum vitamin B6 concentrations were similar between arms. Although not significant between groups, a significant increase over time in erythrocyte magnesium levels was observed in the subgroup of subjects with low baseline erythrocyte magnesium levels (<1.6 mmol/L) following treatment with magnesium and magnesium-vitamin B6 (week 4:0.21 mmol/L [95% confidence interval (CI), 0.10 to 0.31], p = 0.0003; and 0.13 mmol/L [95% CI, 0.02 to 0.23], p = 0.0233, respectively). Change from baseline in circulating vitamin B6 levels at weeks 4 and 8 in the magnesium-vitamin B6 supplemented group (314.96 nmol/L [95%CI, 294.61 to 335.31]) was significantly different (p < 0.0001) compared with the magnesium supplemented group (-0.39 nmol/L [95% CI, -20.73 to 19.94]). Magnesium alone and magnesium-vitamin B6 provided statistically significant increases in erythrocyte magnesium in subjects with low magnesium status (<1.6mmol/L). Vitamin B6 supplementation did not further increase magnesium levels.
... A limited number of clinical studies observed beneficial effects of oral magnesium supplementation on circulating cortisol concentrations. [23][24][25][26] Although evidence regarding the mechanism by which magnesium lowers circulating cortisol levels is somewhat controversial, it might be that the effect is mediated by changes in the hypo- Values are adjusted mean estimates (95% Confidence Intervals) obtained from a one-way ANCOVA with baseline value of the dependent variable as covariate. c Models were additionally adjusted for sex. ...
Objective:
Increasing magnesium intake might reduce the risk of cardiovascular disease (CVD). Whether potential effects on cortisol contribute to these beneficial effects on cardiovascular health remains unclear. We therefore studied effects of long-term oral magnesium supplementation on glucocorticoid metabolism, specifically on the excretion of urinary cortisol, cortisone and their metabolites, as well as on the ratios reflecting enzymatic activity of 11β-hydroxysteroid dehydrogenases (11β-HSDs) and A-ring reductases.
Design:
A post-hoc analysis of a randomized trial with allocation to a magnesium supplement (350 mg/day) or a placebo for 24-week.
Patients:
Forty-nine overweight men and women, aged between 45 and 70 years.
Measurements:
Cortisol, cortisone and their metabolites (tetrahydrocortisol [THF], allo-tetrahydrocortisol [allo-THF] and tetrahydrocortisone [THE]) were measured in 24-h urine samples. Enzymatic activities of 11β-HSD overall and of 11β-HSD type 2 were estimated as the urinary (THF + allo-THF [THFs])/THE and cortisol/cortisone ratios, respectively. A-ring reductase activity was assessed by ratios of THF/allo-THF, allo-THF/cortisol, THF/cortisol and THE/cortisone.
Results:
After 24-week, urinary cortisol excretion was decreased in the magnesium group as compared with the placebo group (-32 nmol/24-h, 95% CI: -59; -5 nmol/24-h, p = .021). Ratios of THFs/THE and cortisol/cortisone were decreased following magnesium supplementation by 0.09 (95% CI: 0.02; 0.17, p = .018) and 0.10 (95% CI: 0.03; 0.17, p = .005), respectively. No effects were observed on A-ring reductase activity.
Conclusions:
We observed a beneficial effect of magnesium supplementation towards a lower 24-h urinary cortisol excretion together with an increased activity of 11β-HSD type 2. Our findings may provide another potential mechanism by which increased magnesium intake lowers CVD risk (ClinicalTrials.gov identifier: NCT02235805).
... Another placebo-controlled randomized crossover study has investigated the effect of Mg supplementation for 20 days on sleep stages (reflecting sleep quality) in twelve older adults, in which electroencephalogram (EEG) and nocturnal hormone secretion were used as measures. It has been found that Mg supplementation resulted in a significant increase in slow-wave (deep) sleep [42]. The effects of Mg on slow-wave sleep were also demonstrated in an animal study that reported decreased slow-wave sleep in Mg deficient rats [43]. ...
Abstract
Purpose: Few previous studies estimated the association between micronutrient status and sleep quality; no previous work was done in patients with depression compared with healthy controls.
Methods: Using a case-control research design, 96 patients with depression were age- and sex-matched with 96 healthy controls. Dietary assessment was done using a standardized questionnaire, and analysis focused on comprehensive 18 micronutrient items. Sleep quality was measured using the Pittsburg Sleep Quality Index (PSQI). Descriptive statistics were used to summarize findings. Logistic regression analysis was used to identify predictors of poor sleep quality.
Results: Patients with depression had a significantly lower sleep quality than controls with a PSQI score of 7.3±2.7 and 5.1±2.5, respectively. The prevalence of poor sleep quality in patients with depression was almost double the prevalence of poor sleep quality in the general population. The micronutrient status of vitamin B12 and Mg successfully predicted sleep quality in healthy controls. However, in patients with depression, micronutrient status failed to predict sleep quality.
Conclusions: The current research showed that sleep quality is positively associated with Mg intake, and negatively associated with vitamin B12 in healthy adults. For patients with depression, sleep quality is not associated with micronutrient intake status. Further research is needed to establish a safe and adequate intake of micronutrients to improve sleep and/or depressive symptoms in patients with depression.
Keywords: adjustment disorders; dietary intake; foods; mood; minerals; vitamins.
... It has also been revealed that iron deficiency may lead to restless leg syndrome or periodic limb movement disorder, which can cause sleep distruption [15]. Oral magnesium supplementation improved total sleep duration and sleep quality in two separate studies with approximately 10 participants having low magnesium status [84,85]. Magnesium, zinc and melatonin found that supplementation improved sleep quality. ...
Sleep duration and quality are associated with many diseases. Evaluating the relationship between nutrient intake and sleep quality is important, because dietary factors play an important role in sleep quality. Short sleep duration which is associated with both metabolic disorders, obesity and, an irregular sleep pattern are thought to be related to an unhealthy diet. The recent literature has been reviewed using EMBASE, PsycARTICLES, PsycINFO, PubMed, ScienceDirect, and Web of Science databases. The effects of macronutrients and micronutrients on sleep parameters have been demonstrated. Carbohydrates and fats can regulate sleep quality by affecting the duration of Rapid Eye Movement (REM) and non-REM sleep. For proteins, tryptophan is the most promising amino acid for sleep-promoting food, since it is the precursor of melatonin and serotonin playing a role in improving sleep quality of humans. It is a common finding that those who have short sleep duration take in more energy from fat and carbohydrate. However, to what extent diet can affect sleep still remains unclear. This present review discusses the potential role of nutrition in regulating sleep quality and offers suggestions for feasible future studies. Some macro and micronutrients of the diet were found correlated with sleep duration and quality. Mechanisms mediating the relationship between sleep duration and dietary intake are multi-factorial. Therefore, future studies will benefit from assessing sleep duration/quality and dietary intake.
... 12 elderly participants showed that magnesium supplementation significantly reversed electroencephalogram changes, including decreased slow-wave sleep, that may occur during ageing. 60 Furthermore, a double-blind trial reported that intraoperative infusion of magnesium significantly improved quality of sleep during the postoperative period, without any side effects. 28 Magnesium is an abundant mineral, naturally present in food, and is available as a dietary supplement that is appreciated by patients. ...
Introduction
Breast cancer affects 1 in 10 women worldwide, and mastectomy is a cause of chronic pain with neuropathic characteristics. N -methyl-D-aspartate receptor (NMDAR) antagonists such as ketamine, memantine, dextromethorphan or magnesium are used to treat refractory pain by blocking NMDAR. Oral memantine has been shown to prevent postmastectomy pain and cognitive impact and to maintain quality of life. Likewise, the present study is intended to assess the preventive effect of oral magnesium, administered ahead of mastectomy, on the development of neuropathic pain. As a physiological blocker of NMDAR, magnesium could be an interesting candidate to prevent postoperative pain and associated comorbidities, including cognitive and emotional disorders, multiple analgesic consumption and impaired quality of life.
Methods and analysis
A randomised double-blind controlled clinical trial ( NCT03063931 ) will include 100 women with breast cancer undergoing mastectomy at the Oncology Hospital, Clermont-Ferrand, France. Magnesium (100 mg/day; n=50) or placebo (n=50) will be administered for 6 weeks, starting 2 weeks before surgery. Intensity of pain, cognitive and emotional function and quality of life will be assessed by questionnaires. The primary endpoint is pain intensity on a 0–10 numerical rating scale at 1 month postmastectomy. Data analysis will use mixed models; all tests will be two-tailed, with type-I error set at α=0.05.
Ethics and dissemination
The study protocol and informed consent form were approved in December 2016 by the French Research Ethics Committee (South East VI Committee). Results will be communicated in various congresses and published in international publications.
Trial registration number
NCT03063931 .
... Результаты клинических исследований показали, что терапия магниевыми препаратами предотвращает вызванное стрессом повышение АД, снижает концентрацию маркеров системного воспаления, увеличивает чувствительность тканей к инсулину, нормализует липидный спектр сыворотки [40][41][42]. Применение препаратов магния способствует нормализации сна, улучшает состояние психоэмоциональной сферы, снижает уровень тревожности и выраженность вегетативных симптомов [43][44][45]. ...
Stress is one of the main reasons for the exponential growth of most chronic non-infectious diseases. The stress response is a genetically determined nonspecific adaptive mechanism. However, if it is an overly intense and prolonged, it becomes a risk factor for the pathogenesis of cardiovascular and oncological diseases, immunodeficiencies, digestive tract diseases and other pathological conditions. Studies have shown that magnesium deficiency, which develops against the background of stress, repeatedly intensifies its negative manifestations. Magnesium preparations make up the basis of therapeutic and rehabilitation activities in children experiencing stress. Timely correction of magnesium deficiency can increase the resistance against the action of stressors, neutralize or mitigate their damaging effect, and also prevent the development of stress-induced pathology.
... Hence, greater effects can be expected in conditions with acutely or chronically reduced amounts of SWS (e.g., after acute stress and during aging [42][43][44], as observed in the above-mentioned pharmacological study, which indeed revealed larger effects in aged compared to young subjects 22 . In such conditions, enhanced SO activity after closed-loop stimulation might well compensate for respective changes in hormonal release during sleep, encompassing increased cortisol and reduced aldosterone and prolactin levels, which may contribute to the decline not only in immunity, but also in cognitive function in the elderly 21,[45][46][47][48] . Moreover, effects of the stimulation might accumulate with repetitive application across several nights. ...
Sleep is essential for health. Slow wave sleep (SWS), the deepest sleep stage hallmarked by electroencephalographic slow oscillations (SOs), appears of particular relevance here. SWS is associated with a unique endocrine milieu comprising minimum cortisol and high aldosterone, growth hormone (GH), and prolactin levels, thereby presumably fostering efficient adaptive immune responses. Yet, whether SWS causes these changes is unclear. Here we enhance SOs in men by auditory closed-loop stimulation, i.e., by delivering tones in synchrony with endogenous SOs. Stimulation intensifies the hormonal milieu characterizing SWS (mainly by further reducing cortisol and increasing aldosterone levels) and reduces T and B cell counts, likely reflecting a redistribution of these cells to lymphoid tissues. GH remains unchanged. In conclusion, closed-loop stimulation of SOs is an easy-to-use tool for probing SWS functions, and might also bear the potential to ameliorate conditions like depression and aging, where disturbed sleep coalesces with specific hormonal and immunological dysregulations.
... Niacin (vitamin B 3 ) and pyridoxine (vitamin B 6 ) may promote the availability of TRP for the synthesis of neurotransmitter serotonin and the neurosecretory hormone melatonin, and hence improve the sleep onset latency and sleep quality [11]. Magnesium could enhance the secretion of melatonin by stimulating serotonin N-acetyltransferase activity [25], as well as act as a γ-aminobutyric acid agonist to improve sleep [26]. However, inconsistent results were reported in a cross-sectional study among Japanese adults [8]. ...
Limited attention has been paid to the effect of dietary patterns on sleep problems. In the present study, we analyzed the cross-sectional data of 481,242 adults aged 30–79 years from the China Kadoorie Biobank. A laptop-based questionnaire was administered to collect information on food intakes and insomnia symptoms. Logistic regression was used to estimate the odds ratios of each insomnia symptom according to quartiles of each dietary pattern, with adjustment for potential confounders. Two major dietary patterns were derived by factor analysis. The traditional northern dietary pattern was characterized by high intakes of wheat and other staple food, whereas the modern dietary pattern was characterized by high intakes of meat, poultry, fish, eggs, fresh fruit, and dairy products. Both dietary patterns were associated with a decreased prevalence of insomnia symptoms (p for trend < 0.001); after adjustment for potential confounders, individuals who had the highest quartile score of traditional northern dietary pattern were 12%–19% less likely to have insomnia symptoms compared to those in the lowest quartile (odds ratio: 0.81–0.88), and the corresponding values for the modern dietary pattern were 0.89–1.01. Furthermore, interactions of these two dietary patterns on insomnia symptoms were observed. Further prospective studies are needed to elucidate the relationship between diet and insomnia.
... Traditionally, nutritional research has been conducted by analyzing the effects of micro-and macro-nutrients, as well as whole foods, respectively. Micro-nutrients that have been investigated in conjunction with sleep include tryptophan [17], vitamin B6 [18], vitamin B12 [19], vitamin D [20,21], iron [22], and magnesium [23]. While this approach is useful for understanding the mechanism of action of single nutrients, its real-world application is often somewhat limited as these supplements have to be extracted from other food sources or produced in the laboratory. ...
Insomnia is the most common sleep disorder. Although treatments such as cognitive-behavioral therapy have been shown to be effective, there are limitations in terms of effects, accessibility, and cost. It is thus of interest to supplement treatment with more accessible means to increase treatment effects. Little research exists concerning the effects of nutrition on sleep. Kiwi fruit contains rich levels of nutrients, such as antioxidants, flavonoids, carotenoids, anthocyanins, folate, and melatonin, all of which could possibly facilitate sleep. Thus, the purpose of this study was to investigate whether kiwi had beneficial effects on sleep compared to a control fruit chosen on the basis of differences in relevant nutritional content. In this randomized controlled trial, 74 students suffering from chronic insomnia symptoms were instructed to ingest either 130 g of kiwi or pear, the latter comprising the control condition, 1 h before bedtime every day for 4 weeks following 1 week of baseline assessment. Outcome measures consisted of sleep diaries and actigraphy. In addition, we administered the Bergen Insomnia Scale and Pittsburgh Sleep Questionnaire Index. Results showed that on a total of two out of 12 outcome variables (sleep quality and daytime functioning as reported using sleep diary), there was a statistically significant group × time interaction effect favoring the kiwi condition compared to pear. Although there were no such effects using objective measures, the results suggest that kiwi may possess some sleep improving properties. Strengths and limitations of the study are discussed.
Magnesium (Mg2+) is a crucial mineral involved in numerous cellular processes critical for neuronal health and function. This review explores the multifaceted roles of Mg2+, from its biochemical interactions at the cellular level to its impact on cognitive health and behavioral regulation. Mg2+ acts as a cofactor for over 300 enzymatic reactions, including those involved in ATP synthesis, nucleic acid stability, and neurotransmitter release. It regulates ion channels, modulates synaptic plasticity, and maintains the structural integrity of cell membranes, which are essential for proper neuronal signaling and synaptic transmission. Recent studies have highlighted the significance of Mg2+ in neuroprotection, showing its ability to attenuate oxidative stress, reduce inflammation, and mitigate excitotoxicity, thereby safeguarding neuronal health. Furthermore, Mg2+ deficiency has been linked to a range of neuropsychiatric disorders, including depression, anxiety, and cognitive decline. Supplementation with Mg2+, particularly in the form of bioavailable compounds such as Magnesium-L-Threonate (MgLT), Magnesium-Acetyl-Taurate (MgAT), and other Magnesium salts, has shown some promising results in enhancing synaptic density, improving memory function, and alleviating symptoms of mental health disorders. This review highlights significant current findings on the cellular mechanisms by which Mg2+ exerts its neuroprotective effects and evaluates clinical and preclinical evidence supporting its therapeutic potential. By elucidating the comprehensive role of Mg2+ in neuronal health, this review aims to underscore the importance of maintaining optimal Mg2+ levels for cognitive function and behavioral regulation, advocating for further research into Mg2+ supplementation as a viable intervention for neuropsychiatric and neurodegenerative conditions.
Self-treatment with vitamin, mineral, and herbal supplements has become increasingly common among patients for the treatment of psychiatric disorders. Magnesium, in particular, is popular on social media for the treatment of anxiety and insomnia. Meanwhile, preclinical studies support associations between magnesium status, sleep quality, and symptoms of anxiety. The extent to which these claims are evidence-based is unclear. Therefore, a systematic review was performed to provide an updated examination of the clinical evidence on the use of magnesium for the treatment of the above conditions given the popularity of such supplements among patients and the public at large.
A thorough search of the PubMed database was performed and results were systematically reviewed using PRISMA guidelines. The search was limited to anxiety disorders and sleep disorders and included interventional trials only. Exclusion criteria included insufficient (<50 mg/12.5% of recommended daily allowance (RDA)) or unknown magnesium dose, >3 other potentially active compounds present in the formulation, and articles in languages other than English. This query returned 860 articles of which 15 met full inclusion criteria. Eight measured sleep-related outcomes, seven measured anxiety-related outcomes, and one examined both. Sleep quality was measured most frequently using the Pittsburg Sleep Quality Index (PSQI). Anxiety measures included self-reported measures such as the Hamilton Anxiety Scale. The majority of included studies demonstrated improvement in at least one sleep- or anxiety-related parameter. Five out of eight sleep-related studies reported improvements in sleep parameters, while two studies reported no improvements, and one reported mixed results. Five out of seven studies measuring anxiety-related outcomes reported improvements in self-reported anxiety.
Firm conclusions were limited by the heterogeneity of the data and the small number of participants involved in most of the studies. The dosages, formulations, and durations of the magnesium interventions used also differed across studies. Furthermore, some studies included additional, potentially active ingredients, further complicating interpretations. Given the generally positive results across studies, the preponderance of preclinical evidence, and minimal side effects, however, supplemental magnesium is likely useful in the treatment of mild anxiety and insomnia, particularly in those with low magnesium status at baseline. Notably, both negative anxiety trials featured populations with underlying endocrine factors likely contributing to their symptoms (patients with premenstrual symptoms and post-partum women). Nonetheless, larger, randomized clinical trials are needed to confirm efficacy and to establish the most effective forms and dosages of magnesium for the treatment of insomnia and anxiety disorders.
Background and Objective: There is evidence suggesting an association between insomnia and obesity and probable beneficial effects of magnesium supplementation on insomnia. The objective of this study was to determine the effects of dietary magnesium supplementation on the energy intake and weight reduction of insomniac overweight or obese elderly subjects. Materials and Methods: A double-blind randomized clinical trial was conducted on 46 overweight or obese subjects randomly allocated into the magnesium or the placebo group, receiving, daily for 8 weeks, either 500 mg magnesium or a placebo, respectively. Using appropriate questionnaires, data were collected on insomnia (insomnia severity index = ISI), physical activity, and sleep-log at baseline and at the end of the intervention period. In addition, information was obtained on anthropocentric confounding factors and daily intakes of magnesium, calcium, potassium, caffeine, energy form carbohydrates, fat and protein, and total daily energy intake using the 24-hr dietary recall questionnaire for 3 days. The N4 and SPSS software version 16 were used for data analysis, the level of significance being a p-value < 0.05. Results: No significant differences were observed in the assessed variables between the two groups at baseline. As compared to the placebo group, in the experimental group dietary magnesium supplementation brought about statistically significant increases in sleep duration and sleep efficiency, as well as significant decreases in the total energy intake and energy from carbohydrate and fat. The total length of time in bed, morning awakening time, energy from protein, serum magnesium concentration, or body weight were not different between the experimental and the placebo groups. Conclusion: In this study dietary magnesium supplementation resulted in improvements in sleep indices and a decrease in energy intake in elderly subjects. However, it had no beneficial effect on their body weight.
Temperature is the primary abiotic player that regulates and restricts fish physiology and growth. The effects of extreme temperatures on fish vary depending on the severity of the stress and any accompanying conditions. This review discuss the impact of extreme temperature on neuroendocrine, antioxidant status, immune response, heamotology, growth, metabolism and reproductive performance. In addition, the mitigation strategies have been discussed.KeywordsFishesClimate changeEnvironmental stress responsesMitigation strategies
Anxiety disorders affect nearly 20% of young adults aged 18-29 years. First-line treatment for anxiety disorders comprises pharmacotherapy and Cognitive Behavioural Therapy, options often criticised for their low efficacy and safety. In contrast, fish-oil-based supplements comprising omega-3 polyunsaturated fatty acids and supporting nutrients are gaining recognition as safe and effective alternatives. Here we present the protocol for a randomised, double-blind, placebo-controlled trial investigating the effects of a high eicosapentaenoic acid multinutrient supplement on validated measures of anxiety and depression in healthy university students experiencing non-clinical levels of anxiety and depression. The primary outcome is improvement in anxiety compared to the placebo group assessed via the Generalised Anxiety Disorder Assessment-7 scale. The participants will be randomised to active treatment comprising a daily dose of 1125 mg eicosapentaenoic acid, 441 mg docosahexaenoic acid, 330 mg magnesium and 7.5 mg vitamin E, or placebo, for 24 weeks, and will complete validated questionnaires and tablet-based tasks sensitive to mood at baseline and end of intervention. Circulating fatty acids and key biomarkers will also be assessed. The students will be genotyped for polymorphisms thought to influence the relationship between long-chain omega-3 polyunsaturated fatty acids and affect. Trial registration; ClinicalTrials.gov, NCT04844034.
Introduction.Stress and stress-induced disorders are not uncommon in pediatric practice. The range of causal stressors (information environment, gadgets, pandemic, armed conflicts, etc.) has expanded significantly these days. The article depicts the main clinical manifestations of stress reactions, pathogenetic mechanisms of their development, provides rational approaches to the therapy of elimination of stress manifestations and consequences in children and adolescents from a pediatric perspective.
Objective:To study the influence of stress on the psychoemotional sphere and cognitive functions in children aged 7 to 9 years from the armed conflict zone in the Donbass.
Materials and methods. 234 children of primary school age were included in the study, of whom 123 children had lived at the armed conflict zone in Donbass for a year. The psychoemotional state and cognitive functions status were determined by children’s tests using a scoring method to assess test results.
Results and discussion.The tests with a scoring method to assess test results showed that 100% of children from the armed conflict zone had a chronic stress, 63% had a moderate to severe stress, a high frequency of various types of phobias, as well as impaired concentration and memory.
Therapeutic approaches to the management of stress reactions directly depend on the cause and clinical manifestations of such reactions. The therapy strategy includes among other things general strengthening actions, psychotherapy, symptomatic and pathogenetic methods of treatment. In addition, both acute and chronic stress leads to intracellular magnesium deficiency and increased urinary magnesium wasting, as a large amount of catecholamines is released under stress conditions, which contributes to shifting magnesium out of cells. The magnesium deficiency results in increased permeability of cell membranes for calcium ions, which creates conditions for electrical instability and excessive excitability of cells, most significantly of neurons. This is reflected in the fact that the process of excitation prevails over inhibitory reactions, and stress reactions develop as the clinical manifestations. It has been established that an adequate balance of magnesium increases the adaptive capabilities in people. Its neurotropic effects made it possible to consider magnesium as an effective pathogenetic agent that can increase stress resistance, stress management, and activate the body’s adaptive reserves.
Conclusion. The causal stressors are manifold, the paediatrician has to deal with stress reactions in children much more often than doctors of other specialties. Magnesium supplements currently form the basis of treatment and rehabilitation actions in children with stress.
Objective
Recent researches suggest that there is a relationship between the pathogenesis of depression and serum Brain Derived Neurotrophic Factor (BDNF) levels. Therefore, the purpose of this clinical trial was to determine effect of magnesium supplementation on serum Level of BDNF, magnesium and depression status in patients with depression.
Methods
A double blind randomized clinical trial was conducted on 46 depressed subjects. The participants were randomly allocated into the magnesium (MG) and the placebo (PG) group and received 500 mg magnesium and placebo daily for 8 weeks. Beck’s test was conducted and blood samples were taken at baseline and after the intervention period for analysis of serum magnesium and BDNF.
Results
No significant differences were observed in assessed variables between the two groups at the baseline. At the end of intervention, supplementation with magnesium oxide had a significant effect on Beck’s test (P=0.01) and serum magnesium (P=0.001), but had no significant effect on BDNF levels (P=0.507) between the two groups.
Conclusions
Daily intake of 500 mg magnesium oxide for at least 8 weeks improved Beck’s test score and serum magnesium in depressed patients, but had no significant effect on BDNF levels between the two groups, Which Further research is recommended.
Objectives: The objective of this study was to determine the effects of dietary magnesium supplementation on mental health in elderly individuals with insomnia. Method: A double-blind randomized clinical trial was conducted on 46 elderly subjects with insomnia randomly allocated to the magnesium or placebo (control) group. The groups received either 500 mg elemental magnesium or placebo, respectively, daily for eight weeks. General Health Questionnaire-28 (GHQ-28) and Insomnia Severity Index (ISI) were conducted at baseline and at the end of the intervention period. Serum magnesium and cortisol levels were also determined in the participants. In addition, information was obtained on anthropometric confounding factors and daily intake of magnesium, calcium, potassium and caffeine using the 24-hour Recall Questionnaire. The "Nutritionist 4" software was used for nutritional analysis. Statistical analysis was done using paired t-test to compare within-groups differences and Student's t-test to compare between-groups differences. Results: No significant differences were observed in the assessed variables between groups at baseline. Compared to the placebo group, dietary magnesium supplementation in the experimental group brought about statistically significant decreases in total GHQ-28 score (p=0.01), somatic symptoms (p=0.04), anxiety/insomnia symptoms (p=0.02), depression symptoms (p=0.001), Insomnia Severity Index (p=0.006), and serum cortisol concentration (p=0.008). Conclusion: Magnesium supplementation can affect some indices of mental health and insomnia and may hence result in improvements in general mental health in elderly people with insomnia.
The systems biology study of the current epidemic of chronic disease has exposed significant pathophysiology related to disorders of the circadian rhythm. Most commonly recognized are sleep disorders within the science of sleep medicine. The master biological clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus gland and is governed by light cues through the retina. It influences a wide variety of functions, including sleep, arousal, feeding, and a myriad of metabolic processes. The focus of this chapter is to present evidence for the influences that nutrients and lifestyle have on the 24-hour circadian rhythm cycle and to provide tools to enable nutritional interventions to help an individual to bring a balance toward wellness. Diet and lifestyle factors influencing sleep and circadian rhythm are sleep quality, nutrient timing and composition, B vitamins, minerals, fats, and phytonutrients, as well as light, melatonin, and sleep habits. Optimizing these factors has been shown as effective treatment for sleep disorders. Food has been shown to have a strong effect on circadian rhythms. If the composition and timing of food eaten are not in phase with the light-dark cycle, a disruption in metabolism can occur. Modern lifestyle, with artificial light and erratic eating patterns, can upset the biological circadian system. Many questions remain unanswered regarding chrononutrition, and there is a need for further human studies. A continuing partnership between chronobiologists and nutritionists will shed light on the connection between nutrition and the circadian system, with the ultimate goal of reducing the burden of chronic diseases.
A wide variety of plant species provide edible seeds. Seeds are the dominant source of human calories and protein. The most important and popular seed food sources are cereals, followed by legumes and nuts. Their nutritional content of fiber, protein, and monounsaturated/polyunsaturated fats make them extremely nutritious. They are important additions to our daily food consumption. When consumed as part of a healthy diet, seeds can help reduce blood sugar, cholesterol, and blood pressure.
Chronische Blasenschmerzen sind eine diagnostische und therapeutische Herausforderung. Neben einer Vielzahl von Ursachen sind insbesondere das „painful bladder syndrome“ mit seiner Sonderform, der interstitiellen Zystitis, sowie der chronisch-rezidivierende Harnwegsinfekt zu bedenken und voneinander zu differenzieren. In der vorliegenden Übersicht werden diagnostische und therapeutische Prinzipien beider Krankheitsbilder beleuchtet.
Sleep disorders are a significant issue in the nursing home population, with prevalence rates from 6% to 65%. They can lead to several deleterious effects, such as increasing malaise, falls, and cognitive decline. There are a variety of treatment options, with nonpharmacologic interventions being first line. If nonpharmacologic measures fail, pharmacotherapy can be considered. Melatonin agonists, select antidepressants, suvorexant, and magnesium supplements have data to upport their use in the elderly patient with minimal side effects. Medications with safety profiles that indicate the risks may outweigh the benefits should be avoided. These include benzodiazepines, nonbenzodiazepine hypnotics, antihistamines, antipsychotics, and most tricyclic antidepressants. Additionally, the lowest effective dose of any medication is recommended to minimize adverse effects.
The 2015 Dietary Guidelines Advisory Committee indicated that magnesium was a shortfall nutrient that was underconsumed relative to the Estimated Average Requirement (EAR) for many Americans. Approximately 50% of Americans consume less than the EAR for magnesium, and some age groups consume substantially less. A growing body of literature from animal, epidemiologic, and clinical studies has demonstrated a varied pathologic role for magnesium deficiency that includes electrolyte, neurologic, musculoskeletal, and inflammatory disorders; osteoporosis; hypertension; cardiovascular diseases; metabolic syndrome; and diabetes. Studies have also demonstrated that magnesium deficiency is associated with several chronic diseases and that a reduced risk of these diseases is observed with higher magnesium intake or supplementation. Subclinical magnesium deficiency can exist despite the presentation of a normal status as defined within the current serum magnesium reference interval of 0.75-0.95 mmol/L. This reference interval was derived from data from NHANES I (1974), which was based on the distribution of serum magnesium in a normal population rather than clinical outcomes. What is needed is an evidenced-based serum magnesium reference interval that reflects optimal health and the current food environment and population. We present herein data from an array of scientific studies to support the perspective that subclinical deficiencies in magnesium exist, that they contribute to several chronic diseases, and that adopting a revised serum magnesium reference interval would improve clinical care and public health.
The effect of age on sleep and the sleep EEG was investigated in middle-aged men (mean age: 62.0 years) and in young men (mean age: 22.4 years). Even though the older men reported a higher number of nocturnal awakenings, subjective sleep quality did not differ. Total sleep time, sleep efficiency, and slow wave sleep were lower in the middle-aged, while stage 1 and wakefulness after sleep onset were higher. The difference in wakefulness within nonREM-REM sleep cycles was most pronounced in the third and fourth cycle. In the older men, EEG power density in nonREM sleep was reduced in frequencies below 14.0 Hz, whereas in REM sleep age-related reductions were limited to the delta-theta (0.25-7.0 Hz) and low alpha (8.25-10.0 Hz) band. Slow-wave activity (SWA, power density in the 0.75-4.5 Hz range) decreased in the course of sleep in both age groups. The between-group difference in SWA diminished in the course of sleep, whereas the difference in activity in the frequency range of sleep spindles (12.25-14.0 Hz) increased. It is concluded that frequency and state specific changes occur as a function of age, and that the sleep dependent decline in SWA and increase in sleep spindle activity are attenuated with age.
Neurons of the medial pontine reticular formation (mPRF) are involved in the execution of numerous behaviors including initiation of locomotion, eye movements, startle responses, and rapid eye movement sleep phenomena. Approximately half of the afferent projections to mPRF neurons come from within the reticular formation (Shammah-Lagnado et al., 1987). In spite of the importance of reticulo-reticular connections, virtually nothing is known about transmitters mediating these synapses. In order to identify a candidate excitatory neurotransmitter, the actions of excitatory amino acids (EAAs) on the membrane properties of mPRF neurons recorded in rat brainstem slices in vitro were studied. Standard intracellular recording methods, including single-electrode voltage clamp, were used to examine the postsynaptic actions of EAAs. We also tested whether EAA antagonists block EPSPs evoked by stimulation of the contralateral reticular formation in the slices. mPRF neurons responded to both non-NMDA and NMDA agonists. NMDA-induced conductances were voltage dependent and depressed by physiological concentrations of magnesium. Stimulation of the contralateral reticular formation elicited EPSPs that were depressed by the general EAA antagonist kynurenate. Evoked EPSPs were partially depressed by 6,7-dinitroquinoxaline-2,3-dione. The evoked EPSP was further reduced by the NMDA antagonist (+/-)-2-amino-5-phosphonopentanoic acid in some cases. These results suggest that excitatory reticulo-reticular neurotransmission is mediated by an EAA. Both non-NMDA and NMDA receptors contribute to EAA neurotransmission in the mPRF formation and play an integral role in reticular formation function.
Young and aged Fischer 344 rats were tested on the place and cue versions of the Morris water maze task. Although all of the young animals reached criterion within the 8-day testing period, the aged animals could be divided into two groups on the basis of their performance to criterion: achievers and nonachievers. Upon completion of the water maze testing, the animals were sacrificed, and their brains were processed for in vitro autoradiography of hippocampal excitatory amino acid receptors. Significant differences were found between the young and old rats in the levels of N-methyl-D-aspartate, CPP, kainate, and AMPA binding in subregions of the hippocampus. Despite the age-related decline in hippocampal glutamate receptors, no relationship was observed between the density or distribution of excitatory amino acid receptors and performance on the water maze task in the aged rats.
Reduced magnesium (Mg) levels have been reported in women affected by premenstrual syndrome (PMS). To evaluate the effects of an oral Mg preparation on premenstrual symptoms, we studied, by a double-blind, randomized design, 32 women (24-39 years old) with PMS confirmed by the Moos Menstrual Distress Questionnaire. After 2 months of baseline recording, the subjects were randomly assigned to placebo or Mg for two cycles. In the next two cycles, both groups received Mg. Magnesium pyrrolidone carboxylic acid (360 mg Mg) or placebo was administered three times a day, from the 15th day of the menstrual cycle to the onset of menstrual flow. Blood samples for Mg measurement were drawn premenstrually, during the baseline period, and in the second and fourth months of treatment. The Menstrual Distress Questionnaire score of the cluster "pain" was significantly reduced during the second month in both groups, whereas Mg treatment significantly affected both the total Menstrual Distress Questionnaire score and the cluster "negative affect." In the second month, the women assigned to treatment showed a significant increase in Mg in lymphocytes and polymorphonuclear cells, whereas no changes were observed in plasma and erythrocytes. These data indicate that Mg supplementation could represent an effective treatment of premenstrual symptoms related to mood changes.
An analysis of data by sleep cycle was carried out for the main variables concerning sleep with EEG slow waves (SSW), sleep with rapid eye movements, and awakenings. Data were presented for six age groups with mean ages of 7·4, 13·8, 21·6, 31·5, 55·3, 77·3 yr. While these data represent the first detailed statistical description of cycle changes with age, the results obtained are consistent with earlier observations. For SSW pronounced age changes occured in the first cycle; durations and rates of change across cycles 2–5 were highly similar for all six age groups. The changes with age in cycle 1 were attributed to the changing level of stage 4 EEG with age.Except for the oldest group, SREMP durations increased from cycle 1 to cycle 3, after which there was little change. In elderly subjects, the first SREMP was equal in length to succeeding periods. The trends across the night for eye movement activity were similar to those for SREMP duration; i.e., these trends showed increases from the first to third cycle for all groups except the oldest.It was suggested that the trends in sleep pattern across the night have significant implications for the brain processes which underlie the electrophysiological manifestations of sleep. A speculative hypothesis was advanced to account for the cyclical nature of sleep, the trends in cycles across the night, and the effects of age on these variables. This hypothesis proposes that the function of sleep with rapid eye movements is to provide a substrate or co-factor required to promote maximal occurrence of sleep with slow waves. Many data in the literature may be viewed as consistent with this hypothesis.
Correlations between cerebral monoamine metabolism and electrophysiological parameters were compared in 18 male Wistar rats subjected to a magnesium-restricted diet and in 14 normal rats. During the 40-day experimental period, plasma and erythrocyte Mg2+ levels and plasma Ca2+ and phosphorus levels were measured, and electroencephalographic tracings as well as clinical data were recorded at regular intervals. At the end of the study, the animals were killed and cerebral concentrations of monoamines and their metabolites were determined. Cerebral monoamine disorders characterized by a rise of dopamine and 5-hydroxyindole-3-acetic acid levels were observed in the magnesium-deficient group. This rise was accompanied by an increase in wakefulness and a decrease in sleep percent. The role played by magnesium in cerebral monoamine metabolism and sleep cycles is discussed.
The responses of vertebrate neurones to glutamate involve at least three receptor types. One of these, the NMDA receptor (so called because of its specific activation by N-methyl-D-aspartate), induces responses presenting a peculiar voltage sensitivity. Above resting potential, the current induced by a given dose of glutamate (or NMDA) increases when the cell is depolarized. This is contrary to what is observed at classical excitatory synapses, and recalls the properties of 'regenerative' systems like the Na+ conductance of the action potential. Indeed, recent studies of L-glutamate, L-aspartate and NMDA-induced currents have indicated that the current-voltage (I-V) relationship can show a region of 'negative conductance' and that the application of these agonists can lead to a regenerative depolarization. Furthermore, the NMDA response is greatly potentiated by reducing the extracellular Mg2+ concentration [( Mg2+]o) below the physiological level (approximately 1 mM). By analysing the responses of mouse central neurones to glutamate using the patch-clamp technique, we have now found a link between voltage sensitivity and Mg2+ sensitivity. In Mg2+-free solutions, L-glutamate, L-aspartate and NMDA open cation channels, the properties of which are voltage independent. In the presence of Mg2+, the single-channel currents measured at resting potential are chopped in bursts and the probability of opening of the channels is reduced. Both effects increase steeply with hyperpolarization, thereby accounting for the negative slope of the I-V relationship of the glutamate response. Thus, the voltage dependence of the NMDA receptor-linked conductance appears to be a consequence of the voltage dependence of the Mg2+ block and its interpretation does not require the implication of an intramembrane voltage-dependent 'gate'.
The responses of vertebrate neurones to glutamate involve at least three receptor types. One of these, the NMDA receptor (so called because of its specific activation by N-methyl-D-aspartate), induces responses presenting a peculiar voltage sensitivity. Above resting potential, the current induced by a given dose of glutamate (or NMDA) increases when the cell is depolarized. This is contrary to what is observed at classical excitatory synapses, and recalls the properties of 'regenerative' systems like the Na+ conductance of the action potential. Indeed, recent studies of L-glutamate, L-aspartate and NMDA-induced currents have indicated that the current-voltage (I-V) relationship can show a region of 'negative conductance' and that the application of these agonists can lead to a regenerative depolarization. Furthermore, the NMDA response is greatly potentiated by reducing the extracellular Mg2+ concentration [( Mg2+]o) below the physiological level (approximately 1 mM). By analysing the responses of mouse central neurones to glutamate using the patch-clamp technique, we have now found a link between voltage sensitivity and Mg2+ sensitivity. In Mg2+-free solutions, L-glutamate, L-aspartate and NMDA open cation channels, the properties of which are voltage independent. In the presence of Mg2+, the single-channel currents measured at resting potential are chopped in bursts and the probability of opening of the channels is reduced. Both effects increase steeply with hyperpolarization, thereby accounting for the negative slope of the I-V relationship of the glutamate response. Thus, the voltage dependence of the NMDA receptor-linked conductance appears to be a consequence of the voltage dependence of the Mg2+ block and its interpretation does not require the implication of an intramembrane voltage-dependent 'gate'.
Assessed hippocampal N-methyl-D-aspartate (NMDA) receptor binding in young and aged rats, using the potent NMDA antagonist 3H-3-[(±)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP), and spatial learning deficits. 3H-CPP bound selectively to receptors in hippocampal tissue with high affinity (39.5 nM). The 3H-CPP receptor binding capacity was significantly reduced in experimentally naive Ss (aged 24–25 mo) as compared with young Ss (aged 5 mo). Similarly, 3H-CPP binding was reduced in aged vs young Ss trained on a spatial task in the Morris water maze. The reduction was correlated with the severity of the learning deficit present within the aged group. A reduction in hippocampal NMDA sites (3H-CPP binding) appears to contribute to cognitive deficits in aged Ss. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
During the first half of nocturnal sleep, the secretory response of the pituitary-adrenal axis to either CRH or vasopressin (VP) administration is reduced. Two experiments were performed aiming (i) to investigate the impact of sleep on the response to a combined CRH/VP administration and (ii) to specify the onset of sleep associated pituitary-adrenal suppression and its relation to specific sleep stages. In experiment I, we compared the effect of simultaneous administration of VP (0.5 IU i.v., within 6 min) and CRH (50 μg bolus i.v., in the third min of VP infusion) on the secretion of ACTH, cortisol and GH in healthy men during the first nocturnal epoch of slow wave sleep (SWS) and during nocturnal wakefulness. The increase of ACTH and cortisol concentrations after combined VP/CRH administration was distinctly higher during wakefulness than sleep (P<0.01). In experiment II, CRH (30 μg/h, after an initial bolus of 30 μg) was continuously infused in 7 healthy men on 2 nights. On one of the nights, the men were allowed to sleep (between 23.00 h and 05.00 h) after a 3-h period of wakefulness, on the other night they stayed awake throughout the experiment. In both conditions, CRH enhanced ACTH/cortisol plasma levels. Compared with concentrations during continuous wakefulness, sleep and in particular SWS was associated with a suppression of ACTH/cortisol levels (P<0.05). The findings further support an inhibitory influence of early nocturnal sleep on pituitary-adrenal activity. The effect appears to be strongest during SWS and is probably mediated via hypothalamic secretion of a release inhibiting factor of ACTH.
This study aimed to characterize the influence of endogenous angiotensin II on renal renin gene expression during different
states of a stimulated and of a suppressed renin system. To this end the renin system in male Sprague Dawley rats was stimulated
by unilateral renal artery clipping (0.2 mm clip), by furosemide (60 mg/kg per diem) or isoproterenol (160 μg/kg per diem),
and by ingestion of a low-salt diet (0.02%), or was suppressed by setting a contralateral renal artery clip (0.2-mm clip)
or by ingestion of a high-salt diet (4%). During the last 2 days of these different treatment regimens, the animals were treated
with the angiotensin II AT1 receptor antagonist losartan (40 mg/kg per diem) and renal renin mRNA levels were assayed. Renin
gene expression was stimulated four- to fivefold by renal artery clipping and isoproterenol infusion, two- to threefold by
furosemide and a low-salt diet, and about fourfold by losartan. Additional treatment with losartan potentiated the stimulatory
effects of a low-salt diet, of furosemide and of isoproterenol infusion on renin gene expression, whilst there was no significant
additional effect of losartan on renin gene expression in clipped kidneys. Both contralateral renal artery clipping and a
high-salt diet decreased renin mRNA levels to about 50% of the control value. In rats with a unilateral clip, additional losartan
treatment caused renin mRNA to increase to about 350% of the control value in the contralateral kidney but to only 110% of
the control value in animals on a high-salt diet. These findings suggest that the enhanced formation of angiotensin II during
a low-salt intake, during tubular inhibition of salt reabsorption or during β-adrenoreceptor activation plays a relevant negative
feedback role in the activation of the renin gene. Moreover, in rats with one hypoperfused kidney, angiotensin II could be
involved in the inhibition of renin gene expression in the contralateral kidney. In hypoperfused kidneys, however, and in
animals on a high-salt diet, angiotensin II appears to play only a minor feedback role in the regulation of the renin gene.
Changes in the sleep-waking cycle of freely moving cats were studied during application of excitatory amino acid antagonists in the ventro-posterolateral thalamic nuclei by microdialysis. dl-2-Amino-5-phosphono-pentanoic acid (APV), a selective (NMDA) receptor antagonist, produced an increase in the deep stages of slow wave sleep and in paradoxical sleep and a decrease in the light stages of slow wave sleep (SWS1), while 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), at a concentration selective for the non-NMDA receptors, produced a marked increase in SWS1. These results indicate a strong sleep-promoting action of excitatory amino acid antagonists and suggest that thalamic NMDA and non-NMDA receptors may play different roles in sleep regulation. Thus, changes in the sleep-waking cycle should be carefully evaluated when assessing the potential clinical use of excitatory amino acid antagonists.
The influence of aging on the renin-angiotensin-aldosterone system was evaluated by comparing young (20 to 30 yr) with elderly (62 to 70 yr) healthy subjects. Despite comparable body sodium-fluid balance in the two age groups, serum renin concentration, plasma renin activity and aldosterone concentrations were lower in the elderly. The age-related decreases in circulating renin and aldosterone concentrations were slight while subjects were supine and receiving normal sodium intake; when upright and during sodium depletion, they were more pronounced. Inverse renin-blood pressure interrelations were noted during two of four study conditions involving normal sodium intake or mild sodium depletion (r = --0.44 and --0.47, respectively), but not during progressive sodium depletion. Plasma renin levels were decreased in the elderly regardless of the presence or absence of an inverse relationship with blood pressure. Aldosterone and cortisol responses to corticotropin infusion were unaltered in the elderly. It is concluded that aging may cause a decrease in circulating renin, with parallel lowering of plasma aldosterone concentrations.
Although exogenous angiotensin II (AII) exerts a multitude of effects on the central nervous system, there is little evidence supporting a physiological role for the endogenously produced peptide. Some investigators have tested the hypothesis that AII is physiologically active in the brain with intracerebral infusions of blockers of the renin-angiotensin system. If blocker infusions produce effects that are opposite to exogenous AII infusions, it is evidence supporting a physiological role for endogenously generated angiotensin. Previous work has demonstrated that intraventricular infusion of AII elicits thirst and stimulates antidiuretic hormone and ACTH release. Intracerebral administration of AII also suppresses aldosterone secretion. Experiments that employed the blockers saralasin, a competitive inhibitor of AII, and SQ 20881, a converting enzyme blocker, are presented; results suggest that endogenous AII is involved in the control of thirst and peripheral hormone levels. Infusion of the blockers in the ventricular system led to changes in peripheral hormone concentrations opposite to that observed following infusions of AII.
This investigation suggests that lithium and magnesium exert different effects on plasma calcium. Since increased calcium concentrations are associated with depression, and decreases in calcium are associated with the relief of depression, the following emerges as a possible explanation for lithium's mode of action. Lithium administration may increase plasma magnesium and calcium. The increase in magnesium alone or in both of these ions may specifically exert an antimanic effect. Secondarily, magnesium may decrease plasma calcium, exerting an antidepressant effect.
Hypermagnesaemia is a well-known but as yet unexplained concomitant of lithium treatment. Prior suggestions implicating a role for aldosterone in magnesium homoeostasis prompted this study of plasma renin, plasma aldosterone and serum magnesium in 17 maniodepressive patients on long-term lithium treatment. In addition to hypermagnesaemia (P less than 0.001), this group of patients had raised plasma levels of aldosterone (P less than 0.001) and increased plasma renin concentration (P less than 0.05). Serum magnesium was positively correlated to plasma aldosterone (r = 0.58, P less than 0.02). The relation between activation of the renin-aldosterone system and the presence of hypermagnesaemia during chronic lithium treatment could conceivably be mediated through a lithium-induced hypovolaemic state.
Nineteen patients with senile brain disease (including 2 with parkinsonian symptoms) were treated with amantadine in an oral dosage of 200--300 mg daily. Seven showed definite clinical benefits such as increased alertness and decreased agitation, and 2 others showed slight benefits. However, in only one instance was the benefit maintained without complications. Toxic effects such as overactivity, anxiety and visual hallucinations were observed in 8 patients. Withdrawal effects (e.g., lethargy and staggering) occurred when amantadine was discontinued. The electroencephalograms (EEGs) of all 19 patients showed a frequency increase, chiefly of occipital alpha activity, and sometimes a return to normal, irrespective of clinical changes. Toxic side effects were associated with particularly prominent EEG acceleration. In 10 of the 19 patients, the clinical changes were further validated by by additional psychologic assessments. Although the value of amantadine is limited when given in this way to patients with senile brain disease, it seems important to observe its effects in drug combinations aimed at correction of neurotransmitter imbalances.
Age effect on plasma renin activity (PRA) and PRA classification was studied in young and older normotensive volunteers. Ambulatory PRA was lower in the older age group than in the younger with both on an unrestricted diet and a low-sodium diet. Renal function, aldosterone excretion, and plasma renin substrate were comparable in both groups. Age had a substantial effect on PRA classification. When the young normotensives were controls, 32% (6/19) older normotensives had abnormally low PRA, or "low renin normotension." Similarly, 18% (2/11) of young patients with essential hypertension but 80% (12/15) of older hypertensives had low PRA. When the older volunteers were controls, however, the incidence of low renin hypertension (LRH) decreased to 53% in the older patients. The use of predominantly young controls for defining normal limits of PRA may result in an overestimate of the incidence of LRH and may contribute to the heterogeneity of LRH.
Twenty or more normal subjects (half of whom were males) in each decade of life from age 20 to 80 years were included in the study. Plasma renin activity (PRA) was measured with the subjects on a normal sodium diet and after sodium restriction and standing. Aldosterone and sodium excretion rate was measured on unrestricted sodium intake and on day 3 of sodium restriction. Plasma renin activity was quantitated by both bioassay and radioimmunoassay of angiotensin-I. Plasma renin activity under both test conditions declined with increasing age, especially those over 40. Values of those in the seventh decade averaged 60 per cent of the value of that of the younger age group. Response of renin activity to sodium restriction and standing was 73 per cent of that of the younger age group. Older females tended to be less responsive to sodium restriction and standing. Aldosterone excretion rate declined with increasing age so that by the seventh decade the values averaged 55 per cent of those in the second decade of life. Aldosterone excretion rate in response to sodium restriction also declined with increasing age, particularly above the fourth decade, so that the values on day 3 of sodium restriction in the older subjects averaged 33 per cent of that of the subjects in the second decade of life. Renin substrate did not decline with increasing age. The decline in renin activity and aldosterone values in the older subjects appeared to be due to factors other than sodium or potassium intake.
Magnesium is an essential cofactor for many enzymatic reactions, especially those involved in energy metabolism. Deficits of magnesium are prevalent due to inadequate intake or malabsorption and due to the renal loss of magnesium that occurs in certain disease states (alcoholism, diabetes) and with drug therapy (diuretics, aminoglycosides, cisplatin, digoxin, cyclosporin, amphotericin B). Protracted deficits of magnesium in humans and animals result in neurological disturbances, including hyperexcitability, convulsions and various psychiatric symptoms ranging from apathy to psychosis, some of which can be reversed with magnesium supplementation, others requiring correction of the dysregulation mechanism. Although the role of magnesium in neuronal function is not completely understood, a lowering of CSF or brain magnesium can induce epileptiform activity and there is an association between decreased CSF magnesium and the development of seizures. CSF concentrations of magnesium are normally higher than magnesium plasma ultrafiltrate (diffusible) concentrations due to the active transport of magnesium across the blood-brain barrier. Under conditions of magnesium deficiency, CSF concentrations decline, although this decline lags behind and is less pronounced than the changes observed in plasma magnesium concentrations. Decreases in CSF magnesium concentrations correlate with the alterations observed in extracellular brain magnesium concentrations in animals following the dietary deprivation of magnesium. CSF magnesium concentrations can readily be repleted following magnesium supplementation, although high dose magnesium therapy, such as that used in the treatment of convulsions in eclampsia, will only increase CSF magnesium concentrations to a very limited degree (approximately 11-18 per cent) above physiological concentrations. Greater increases in CSF magnesium may occur in neonates since neonatal swine, following treatment with magnesium, have CSF magnesium concentrations that are similar to their plasma concentrations. There has been a recent resurgence of interest in magnesium deficiency and its neurological consequences due to the finding that magnesium, at physiological concentrations, blocks N-methyl-D-aspartate (NMDA) receptors in neurones. NMDA receptors are normally activated by glutamate and/or aspartate which represent the principal neurotransmitters for excitatory synaptic transmission in vertebrate CNS. Magnesium deficiency produces epileptiform activity in the CNS which can be blocked by NMDA receptor antagonists. Other mechanisms, including alterations in Na+/K(+)-ATPase activity, cAMP/cGMP concentrations and calcium currents in pre- and postsynaptic membranes, may also be at least partially responsible for the neuronal effects associated with low brain magnesium. Further studies are necessary to increase our understanding of the neurological implications of magnesium deficit in the central nervous system.
The aim of this study was to elucidate the effects of N-methyl-D-aspartic acid (NMDA) receptor stimulation on the release of several hormones known to be activated during stress. The experiments were performed in conscious freely moving cannulated rats. Systemic administration of N-methyl-D,L-aspartic acid (NMA) and of NMDA in low doses (2.5-10 mg/kg i.p.) was found to induce a dose-related stimulation of adrenocorticotropin (ACTH) release. NMA-induced ACTH release was reduced by administration of an NMDA receptor antagonist (D,L-2-amino-5-phosphonovaleric acid). NMDA was much more potent in activating ACTH release than the racemic form of the amino acid, NMA. In the dose range used, both NMA and NMDA failed to influence prolactin release. With the exception of a small increase in epinephrine concentration in response to the highest dose of NMDA (10 mg/kg), no changes in plasma catecholamines were observed. The data indicate that NMA and NMDA administered in low doses trigger ACTH release without induction of a nonspecific stress response.
The administration of gamma-aminobutyric acid (GABA) in the brain right lateral ventricle reduces serum corticosterone levels, and induces significant variations of hypothalamus biogenic amines in conscious male rats. After pretreatment with either alpha 1-adrenergic (prazosin) or alpha 2-adrenergic (yohimbine) blocking agents, the inhibitory effect of GABA on ACTH secretion was prevented. However, we observed that pretreatment with a beta-adrenergic blocking agent (propranolol), did not preventing the inhibitory effect of GABA on serum corticosterone levels. These results indicate that GABA has an inhibitory effect on ACTH secretion mediated by the activation of alpha 1 and alpha 2-adrenergic receptors.
The efficacy and tolerability of memantine (1-amino-3,5-dimethyl-adamantane hydrochloride, Akatinol Memantine; CAS 41100-52-1) was investigated in a double-blind, randomized clinical study versus placebo in 66 patients aged between 65 and 80 years predominantly suffering from mild to moderate vascular dementia. The target variables assessed were the baseline differences of the Sandoz Clinical Assessment Geriatric scale (SCAG) and Syndrom-Kurz-Test (SKT) total scores and the total time required in the subtests of Activity of Daily Living tests (ADL). Additional parameters assessed were the physician's global impression, the Mini Mental State Evaluation (MMSE), the Tapping and Trace tests for fine motor rating and the quality in performing the ADL tests. Adverse drug effects were recorded by DOTES/TWIS. 59 of the 66 patients included in the study terminated the trial (29 in the placebo and 30 in the memantine group). For the baseline differences of the SCAG total score a statistically significant improvement was observed already after 14 days of memantine treatment as compared to placebo. After 42 days this difference was still more pronounced and highly significant. Significant improvements after 14 and 42 days of memantine treatment could also be demonstrated for the SCAG subscales cognitive disturbances, lack of drive, emotional disturbances, social behaviour and somatic disturbances. Additionally, the efficacy of the drug could be confirmed by the SKT and ADL tests. Particularly striking in the ADL tests was the considerable improvement achieved in the quality of performing the tasks under memantine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Binding activities of central excitatory amino acid receptors were examined in Triton-treated membrane preparations of the cerebral cortex and hippocampus from brains of rats at 2, 7 and 29 months after birth. Aged rats exhibited a significant reduction of [3H]glutamate (Glu) binding displaceable by N-methyl-D-aspartate (NMDA), as well as strychnine-insensitive [3H]glycine binding in both central structures, as compared with those in young rats. Binding of [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne maleate (MK-801), a non-competitive NMDA antagonist used to label the activated state of ion channels linked to NMDA-sensitive receptors, also decreased with aging irrespective of the experimental conditions employed. Scatchard analysis revealed that reduction of both [3H]Glu binding and [3H]MK-801 binding were due to a significant decrease in the densities of binding sites with aging, with their affinities being unaltered. Binding of [3H]D,L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), which is a specific agonist for quisqualate-sensitive receptors, was unchanged with aging when determined in the absence of 100 mM potassium thiocyanate (KSCN). However, AMPA binding determined in the presence of added KSCN was about 25% reduced in both brain regions of aged rats. Binding of [3H]kainate to kainate-sensitive receptors was unchanged with aging. These results suggest that glutaminergic neurotransmission mediated by NMDA-sensitive receptors may be selectively impaired with aging in the hippocampus and cerebral cortex among 3 different subclasses of excitatory amino acid receptors in the brain.
Excitatory amino acids have been known to increase pituitary secretion of LH in vivo and are probably involved in the neuroendocrine regulation of the hypothalamic-pituitary-gonadal axis. We have found that systemic administration of the excitatory amino acid agonist N-methyl-D-aspartate (NMDA) evokes a transient and profound increase in circulating levels of ACTH as well. Treatment of adult male Long-Evans rats with NMDA (30 mg/kg, sc) maximally increased plasma ACTH and immunoreactive beta-endorphin from 7-15 min after injection, and levels of both remained significantly elevated until 60 min into the time course. Corresponding increases in corticosterone were observed 15 and 30 min after treatment, while LH, similar to other pituitary hormones, was increased from 7-30 min after NMDA. Stimulation of the pituitary-adrenal and pituitary-gonadal neuroendocrine axes by NMDA was monitored in subsequent studies by plasma ACTH and LH, respectively; both were increased in a dose-related manner after the administration of 3-60 mg/kg NMDA, although stimulation of ACTH (800%) was more pronounced than that of LH (200%). The increases in ACTH and LH due to NMDA were inhibited by pretreatment with the competitive NMDA antagonist (+/-)3-(2-carboxypiperazin-4- yl)propyl-1-phosphonic acid, CPP (6 and 10 mg/kg, ip, for 21 min); by contrast, dexamethasone pretreatment (50 micrograms/kg, ip, for 4 h) blocked only the NMDA-evoked increase in circulating ACTH. These findings indicate that an NMDA receptor mechanism might be involved in the acute activation of the hypothalamic-pituitary-adrenal axis in the rat.
Angiotensin II (AII) has an important role in the regulation of CRF release. In the present study, the effect of centrally administered AII on CRF messenger RNA (mRNA) levels in the rat hypothalamus was examined. Administration of 0.1 nmol and 1 nmol AII into the lateral ventricle increased the levels of plasma ACTH 20 min and 45 min after administration and those of proopiomelanocortin mRNA in the anterior pituitary (AP) and CRF mRNA in the hypothalamus 2 h after administration. On the other hand, ACTH levels in AP and CRF levels in the median eminence temporarily decreased 45 min after the administration of 1 nmol AII, but it returned to the control level at 90 min. Administration of 10 nmol saralacin, an AII antagonist, blocked 1 nmol AII-induced increase in the levels of plasma ACTH, proopiomelanocortin mRNA in AP, and CRF mRNA in the hypothalamus. These results indicate that central administration of AII increases the CRF mRNA level in the hypothalamus in a receptor-specific manner and also increases CRF release. Therefore, AII seems to have an important role in the regulation of the release and synthesis of CRF in the hypothalamus.
Cortisol modulates brain functions in humans. This principal endogenous glucocorticoid in humans decreases rapid-eye-movement (REM) sleep and increases slow-wave sleep (SWS). Because cortisol exerts its effect on brain functions via mineralocorticoid receptors (MR) and glucocorticoid receptors (GR), we were interested in which type of corticosteroid receptor mediates these steroid effects on sleep. Healthy men were tested in two double-blind experiments. In experiment I (n = 8), the subject's sleep was tested during four nights: 1) after pretreatment with dexamethasone (Dex, 4 mg/day) for 4 or 6 days and after additional infusion of placebo or cortisol (10 mg/h) during the experimental night, 2) after pretreatment with placebo for 4 or 6 days and after infusion of placebo or cortisol (10 mg/h) during the experimental night. In experiment II, subjects (n = 10) slept after intravenous administration of potassium canrenoate (200 mg, at 0800 and 1700 h before experimental nights) or placebo. Cortisol infusion moderately increased the percentage of SWS (P less than 0.05) and markedly decreased REM sleep (P less than 0.01); influence of cortisol on SWS did not depend on pretreatment with Dex. Dex reduced both SWS and REM sleep (P less than 0.05). Canrenoate markedly diminished SWS (P less than 0.01) but left REM sleep unaffected. The results suggest that corticosteroid-induced changes in SWS are mediated via MR-like central receptors in humans, whereas changes in REM sleep involve GR.
To delineate the physiological effects of aging on basal levels and temporal patterns of neuroendocrine secretions, the 24-h profiles of cortisol, thyroid-stimulating hormone (TSH), melatonin, prolactin, and growth hormone (GH) levels were simultaneously obtained at frequent intervals in eight healthy, active elderly men, age 67-84 yr and in eight young male adults, age 20-27 yr. The study was preceded by an extended period of habituation to laboratory conditions, and sleep was polygraphically recorded. Mean cortisol levels in the elderly were normal, but the amplitude of the circadian rhythm was reduced. Circulating levels of daytime and nighttime levels of both TSH and GH were greatly diminished in old age. In contrast, prolactin and melatonin concentrations were decreased during the nighttime only. The circadian rises of cortisol, TSH, and melatonin occurred 1-1.5 h earlier in elderly subjects, and the distribution of rapid-eye-movement stages during sleep was similarly advanced, suggesting that circadian timekeeping is modified during normal senescence. Despite perturbations of sleep, sleep-related release of GH and prolactin occurred in all elderly men. Age-related decreases in hormonal levels were associated with a decrease in the amplitude, but not the frequency, of secretory pulses. These findings demonstrate that the normal process of aging involves alterations in the central mechanisms controlling the temporal organization of endocrine release in addition to a reduction of secretory outputs.
In order to evaluate the impact of aging on EEG sleep patterns we investigated the polysomnograms of 74 patients with major depression and 51 healthy volunteers aged 18-65 years. In most of the EEG sleep parameters, age-related changes were obvious in both the depressives and the normals. In the patients, some of these alterations occurred earlier and were more pronounced. The amount of slow-wave sleep decreased with age, but no differences were found between the depressives and the healthy volunteers at any particular age. Rapid-eye-movement (REM) latency was clearly affected by age, but there were no significant differences between patients and controls until the middle of the fourth decade of life. On the other hand, REM density measures did not vary with age and were increased in the depressives. Therefore, REM density appears to be a more likely candidate for a biologic marker for major depression than is REM latency.
Magnesium status was evaluated in healthy elderly people, and in patients affected from dementia of the Alzheimer type. Magnesium levels were determined in plasma, erythrocytes (RBC), lymphocytes (MNC), and granulocytes (PMN), and were compared with measurements in young healthy adults. Significantly lower plasma Mg concentrations were found in elderly people compared to controls, with no difference between cognitively normal and demented subjects. Mg levels in healthy elderly people were higher in MNC and lower in PMN, compared to the younger group. No difference was observed between demented patients and young controls in Mg content of white blood cells, but the patients had higher Mg/K ratios. In addition, significant correlations were found between cognitive impairment and the Mg/K ratio in MNC. When we assessed the philothermal response of granulocytes, a significant correlation was observed in demented subjects between the migration rate of PMNs and the PMN Mg/K ratio.
This study examined the effects of magnesium on changes in blood pressure and plasma aldosterone concentration (PAC) elicited
by angiotensin II in rats. The infusion of angiotensin II (0.1 nmol/kg/ min) for 30 min increased mean arterial pressure (MAP)
and PAC. Simultaneous infusion of magnesium sulphate (5 μmol/kg/min) attenuated the MAP elevation (157.0 ± 5.2 (SE) v 141.6 ± 3.5 mm Hg, P < .01) and the increase in PAC (447 ± 70 v 233 ± 50 pg/mL, P < .01) brought about by angiotensin II. These effects of magnesium were abolished when endogenous angiotensin II was suppressed
by the administration of captopril, an angiotensin converting enzyme inhibitor. The results suggest that magnesium may attenuate
the biological actions of angiotensin II. Am J Hypertens 1990;3:488-490
Power spectra were used to analyse spontaneous field potentials (SFPs) recorded in the CA3 distal apical dendritic region of guinea pig hippocampal slices perfused with either penicillin or reduced Mg2+. High concentrations of penicillin (2000 IU/ml) progressively converted the low amplitude, irregular oscillations observed in control medium to higher amplitude, low frequency, rhythmic oscillations at approximately 2-3 Hz just prior to the onset of spontaneous, synchronized bursting. Low concentrations (50-300 IU/ml) increased the power of frequencies below 10 Hz and suppressed higher frequencies in a dose-dependent fashion. Although Mg2(+)-free medium also increased the magnitude of the SFPs prior to the onset of synchronous bursting, the changes were smaller than with penicillin and the frequency distribution was completely different. Low concentrations of Mg2+ (0.0-0.5 mM) increased the power across all frequencies, however, the maximal effect was on frequencies between 5 and 25 Hz. The transition from normal to epileptiform activity may proceed through at least 2 distinct intermediate states. When recurrent inhibition is blocked (penicillin), synchronous synaptic activity precedes the onset of bursting, whereas non-specific increases in excitability and activation of NMDA receptors (reduced Mg2+) produce an asynchronous transition state.
1. Nine severe rapid cycling manic-depressive patients were treated with a magnesium preparation, Magnesiocard 40 mEq/day in an open label study for a period up to 32 weeks. 2. Magnesiocard was found to have clinical results at least equivalent to those of lithium in about 50% of these patients. These results were obtained in an exploratory study and should be interpreted with caution. 3. The possibility that Magnesiocard could replace or improve the efficacy of lithium as a preventive treatment of manic-depressive illness merits further clinical investigation.
The effect of lithium on slow wave sleep (SWS) was studied in ten normal male volunteers using home based cassette sleep recording and automatic sleep stage analysis. Lithium increased SWS, an effect consistent with a reduction in brain 5-HT2 receptor function.
We examined the direct effect of magnesium ion on aldosterone production by adrenal cells using collagenase-dispersed zona-glomerulosa cells in rats. The effects of magnesium on aldosterone production stimulated by angiotensin II or ACTH were also investigated. Both magnesium sulphate (MgSO4) and magnesium chloride (MgCl2) (0 to 2 mM) decreased aldosterone production in a dose-dependent manner. In comparison with magnesium-free medium, 2 mM MgSO4 inhibited aldosterone production by 73% and MgCl2 by 65%. In addition, MgSO4 showed an inhibitory effect on aldosterone production stimulated by angiotensin II (10pM to 10nM), whereas it had no significant effect on aldosterone production due to ACTH stimulation (10pM to 10nM). These data suggest that magnesium has an inhibitory action on aldosterone production in vitro and may be a physiological regulator of aldosterone production.
Experiments were performed in anaesthetized cats, to determine whether renal nerves interfere with the negative feedback action of angiotensin II (Ang II) on renin release. The increase in renin release from the innervated kidney in response to captopril-induced inhibition of Ang II generation was compared with the response of the contralateral denervated kidney. Renin release was measured before (control), and 5, 15 and 30 min after the beginning of captopril infusion (1 mg/kg priming dose followed by 1 mg/kg per h for 30 min intravenously), and 60 min after the end of the infusion. During the captopril treatment renin release from both kidneys increased, but after 15 and 30 min the increase in renin release from the innervated kidneys was significantly larger than that observed in the denervated kidneys. After the captopril infusion was stopped, renin release from both kidneys returned towards control values. These results could not be explained on the basis of the changes in renal haemodynamics, excretory functions and efferent renal nerve activity observed during the captopril infusion. The data suggest that the renal nerves influence the changes in renin release caused by captopril by increasing the sensitivity of juxtaglomerular cells to the negative feedback action of Ang II.
This review examines the various research approaches undertaken to investigate possible central nervous system correlates of major depressive illness and relates findings from these studies to the alterations in central nervous system and neuroendocrine function that normally accompany aging in humans. The topics reviewed include: epidemiology of depression and suicide in the elderly; monoamine theories of depression; neuroendocrine disturbances in depression; and imaging studies.
The age-related changes in the renin-angiotensin system were investigated in normotensive 3-, 10-, 20-, and 30-mo-old female Wistar rats. Plasma renin concentration and immunofluorescent renal renin index remained constant from 3 to 10 mo, then decreased as the animals become older, whereas plasma concentration of renin substrate diminished slightly between 10 and 20 mo and plasma converting-enzyme activity was not modified with age. Acute inhibition of converting-enzyme activity by intravenous administration of 0.1 mg/100 g body wt S 9780 (the diacid form of S 9490) was followed by a 7- to 8-mmHg decrease in arterial pressure and a concomitant 10-12% increase in inulin and p-aminohippuric acid (PAH) clearance in the 10- and 20-mo-old rats. On the other hand, neither glomerular filtration rate, PAH clearance nor arterial blood pressure were affected by converting-enzyme inhibition in the 30 mo-old rats. These results indicate that the activity of the renin-angiotensin system is progressively reduced with age and suggest that angiotensin II does not play an important role in the maintenance of blood pressure and kidney hemodynamics in normotensive female senescent rats.
The experiments on adult (4-6 months) and old (28-30 months) rats revealed changes that develop in old age in various links of the regulatory system of aldosterone secretion: the hypothalamic-hypophyseal control of mineralocorticoid secretion decreased, and the sensitivity of the glomerular zone to ACTH, vasopressin, and K+, as well as that of the myocardium, skeletal muscle and kidney to aldosterone increased. Changes in tissue sensitivity to aldosterone may be due to the increased affinity of mineralocorticoid receptors to aldosterone in old age.
The effects of lithium carbonate on sleep patterns have been investigated both acutely in normal and depressed subjects and chronically in depressed subjects. In normal subjects receiving lithium for two weeks total sleep time did not vary, REM sleep decreased and REM sleep latency increased. In depressed subjects, either on short therm therapy or on long term therapy stages 3 and 4 increased, REM sleep decreased, REM latency increased and REM activity/time spent asleep (an index of REM intensity per minute of sleep) decreased. Plasma lithium levels were negatively correlated with REM sleep percentage and positively correlated with REM sleep latency. Besides, it has been shown in one paper that short term therapy with lithium caused small but significant delays in the sleep-wake circadian rhythm. These effects are of interest in view of polygraphic sleep abnormalities found in affective disorders and possible circadian disturbances accounting for these abnormalities. Indeed lithium might act in correcting spezial sleep abnormalities and/or circadian disturbances. In addition to its predominant use for the prophylaxis of recurrent mania and depression, lithium carbonate has been proposed and tried in the prophylactic treatment of abnormally prolonged sleep episodes featuring the Kleine-Levin syndrome.
To investigate the effect of aging on the renin-angiotensin-aldosterone system, plasma renin substrate concentrations (PRSC); plasma total, active, and inactive renin concentrations (TRC, ARC, and IRC); PRA; and plasma aldosterone concentrations (PAC) were measured simultaneously in 60 normal subjects, 18-84 yr old. PRSC was measured by the addition of excess human renal renin. ARC and TRC after trypsin activation were measured by adding sheep renin substrate; IRC was calculated by subtracting ARC from TRC. The active renin ratio was calculated as follows: ARC/TRC X 100%. PRA and PAC were measured by RIA. There were no significant changes in PRSC, TRC, IRC, and PRA to PAC ratio with aging. Both ARC and active renin ratio fell significantly with aging (r = 0.46 and P less than 0.01; and r = 0.54 and P less than 0.01, respectively). PRA and PAC also tended to decrease with aging (r = 0.35 and P less than 0.01; and r = 0.59 and P less than 0.01, respectively). A significant positive correlation was found between PRA and ARC (r = 0.72; P less than 0.001). PRA was also correlated with PAC. In conclusion, the age-related decrease in PRA is not due to the change in PRSC, but is mainly due to the fall in ARC. Decreased conversion of inactive to active renin might be responsible in part for the reduced ARC in the elderly.
Slices of rat cerebral cortex developed spontaneous paroxysmal discharges when superfused with Krebs medium containing zero Mg2+ or 50 microM bicuculline. In both situations, the N-methyl-D-aspartate (NMDA) antagonists APV, 100 microM, and ketamine, 100 microM substantially reduced the frequency of the paroxysmal events, the reduction being greater in zero Mg2+. gamma-Aminobutyric acid (GABA) 1 mM, the GABA-A agonist muscimol 2 microM and the GABA-B receptor agonist baclofen 10 microM, each reduced the frequency of events in zero Mg2+ while muscimol and GABA also reduced the amplitude of the events. GABA and baclofen were similarly effective against bicuculline-induced events but the muscimol concentration required was 5-10-fold higher. These results suggest that, under our vitro conditions, neocortical cells are normally restrained from paroxysmal discharges by Mg2+. Inhibition by GABA through GABA-A receptors and inhibition by GABA through GABA-B receptors, may also contribute to this restraint.
Previous experiments have suggested that sleep processes are sensitive to influences of corticosteroids. The present experiment was designed to compare effects of three different corticosteroids on human sleep: fluocortolone (a synthetic pure glucocorticoid), cortisol which possesses glucocorticoid and mineralocorticoid activity, and aldosterone (the major mineralocorticoid). Ten male adult subjects were tested in four experimental nights according to a double-blind latin-square design under conditions of either 1.0 mg of aldosterone, 20 mg of fluocortolone, 80 mg of hydrocortisone, or placebo. Substances were administered orally (fluocortolone, 23.00 h) or infused iv throughout the night (hydrocortisone, aldosterone) starting at 23.00 h. Hydrocortisone and fluocortolone induced a substantial reduction of rapid eye movement sleep. Hydrocortisone increased slow wave sleep activity. No such effect was observed after fluocortolone. Effects on sleep processes of aldosterone, in general, seemed to be neglegible. The results demonstrate differential effects of synthetic glucocorticoid, cortisol, and aldosterone on sleep in humans, which may be attributed to the heterogeneity of corticosteroid receptors in the brain.
In a prospective study of EEG sleep patterns in 25 elderly depressives, 25 elderly demented patients, and 25 healthy, elderly control subjects, the sleep of depressives was characterized by reduced REM sleep latency, increased REM percent and first REM period density, and altered temporal distribution of REM sleep, as well as by diminished sleep maintenance (correlated significantly with Hamilton ratings of depression: multiple R = -0.42, p less than 0.05). In contrast, the sleep of demented patients showed reduced REM sleep percent, but normal REM temporal distribution, increased loss of spindles and K-complexes (the latter correlating significantly with severity of cognitive impairment as measured by the Folstein score: multiple R = -0.59, p less than 0.01), and less severe sleep maintenance difficulty than for depressives. An examination of REM latency demonstrated a skewed distribution in depression (i.e., 42% of nights with sleep-onset REM periods), but a normal distribution in the controls and demented subjects. A REM latency cut-off score of 30 min correctly classified 68% of all patients (kappa = 0.36; p less than 0.005), compared with 78% correctly identified in our retrospective study (Reynolds et al. 1983).
In forty-four Parkinsonian patients sleep spindles were studied before and during l-DOPA or amantadine therapy.By using a “spindle counter”, based on analysis of harmonic components, spindles were counted automatically.Increase of spindling was observed, less evident in patients after thalamotomy, after 1–2 months of l-DOPA treatment but only in those showing clinical improvement. After 6–24 months of l-DOPA treatment a further spindle increase was noted.Amantadine treatment gave rise to increase in spindling; however, less than that observed after 1–2 months of l-DOPA therapy.This increase in spindling observed in all clinically improved patients confirms previous observations of spindle decrease in Parkinsonism.RésuméLes fuseaux du sommeil ont été étudiés dans quarante-quatre malades Parkinsoniens avant de commencer le traitement par la l-DOPA ou par l'amantadine et à des moments différents du traitement.Le comptage automatique des fuseaux a été effectué par l'appareil “spindle-counter” basé sur l'analyse différentielle des contenus harmoniques instantanés.Après 1–2 mois de traitement par l-DOPA on a observé une augmentation des fuseaux qui n'apparaît que chez les sujets améliorés du point de vue clinique et non chez les Parkinsoniens qui ne présentent aucune amélioration clinique. Parmi les sujets améliorés cette augmentation des fuseaux préalablement soumis à des interventions stéréotaxiques. Après 6 mois à 2 ans de traitement par l-DOPA on a observé une augmentation supplémentaire des fuseaux.Le traitement par l'amantadine induit une augmentation des fuseaux moindre que celle observée chez les Parkinsoniens améliorés après 1–2 mois de l-DOPA.Le caractère constant, chez tous les Parkinsoniens améliorés après traitement par l-DOPA ou amantadine, d'une augmentation du temps de “spindling” confirme les observations précédentes concernant le manque de fuseaux du sommeil chez ces malades.
The concentration gradients of Mg++ and K+ in the cerebrospinal fluid system indicate that the (Mg++) is higher and the (K+) is lower in the extra-cellular fluid of the cerebral cortex than the concentrations of these cations in either plasma-dialysate
or cisternal fluid. Such cation distribution demonstrates the existence of an active transport process across the blood-brain
barrier.
Age-related changes in plasma renin activity (PRA) and in plasma levels of adrenocortical steroids were studied in 140 normotensive men and 128 normotensive women. All were free of disease, and their ages ranged from 20 to 86 years. PRA decreased gradually with age in both men and women, and was slightly lower in women than in men. In the older subjects, the responses of PRA to the administration of furosemide or to dietary sodium restriction plus the upright position for blood sampling were significantly less than in the younger subjects. Apparently the suppression of PRA with age is due either to dysfunction of the juxtaglomerular cells induced by aging, or to reduction in the number of functioning nephrons. The plasma level of aldosterone was also reduced with age, but the levels of desoxycorticosterone, corticosterone, and cortisol were not significantly affected. The suppression of aldosterone seemed to be chiefly dependent upon the suppression of renin activity. However, the possibility remains that disturbed function of the glomerular cells with aging also is related to the suppression of aldosterone, since the response of aldosterone to dietary sodium restriction (upright position for blood sampling), to angiotensin II, and to potassium were greatly reduced.