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Creatine as a booster for human brain function. How might it work?

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... This last hypothesis is based on arguments that in normal healthy individuals with balanced diets, there is no deficit in brain creatine levels [89,110], therefore supplementation has no beneficial effect. However, it has been argued that stressed individuals show decreases in brain creatine and, therefore, benefit from supplementation [89,110,117]. ...
... This last hypothesis is based on arguments that in normal healthy individuals with balanced diets, there is no deficit in brain creatine levels [89,110], therefore supplementation has no beneficial effect. However, it has been argued that stressed individuals show decreases in brain creatine and, therefore, benefit from supplementation [89,110,117]. The stressors we examined were diet (vegans and vegetarians), ageing, hypoxia, sleep deprivation and mental fatigue, as research has been undertaken using these stressors. ...
... These tasks are undoubtedly more difficult than simple attention, perception and memory tests, but there is no evidence to suggest that in normal circumstances, the brain is incapable of producing sufficient energy to ensure optimal performance of such tasks. However, some authors have argued that creatine supplementation may have a positive effect on cognition in stressful situations [89,110]. Moreover, there is empirical support for this, albeit somewhat limited [87,88,111,137]. ...
... Similar to other neurotransmitters, creatine is released in an excitotoxic and action potential-dependent manner. Moreover, it was enhanced by electrical stimulation and blocked by the absence of Ca 2+ or by tetrodotoxin (6). ...
... The Na + , K + -ATPase, a key enzyme in the cell membrane, which is activated by the calcineurin, plays a pivotal role in cellular ionic gradient maintenance and neural excitability (5). It is a critical process for neural functioning and its impairments are associated with several neurological diseases (6). In accordance with this view, it was shown that Na + , K + -ATPase inhibition increased cellular Ca 2+ and glutamate which could cause seizures in mice (16) and cell death in rat hippocampus (17). ...
... Hence, the stimulating effect of creatine on NMDA receptors must be mediated by cellular Ca 2+ and Na + channels and subsequent calcineurin pathway activation (5,6,19,20). These findings demonstrated that creatine supplementation improves learning and memory by a mechanism depending partially on the involvement of NMDA receptors and cellular ionic gradient maintenance (21,22). ...
Article
Creatine is a nutritional compound that potentially influences cognitive processing and neuroprotection. Recent evidence has demonstrated that similar to neurotransmitters, creatine is released in an excitotoxic and action potential-dependent manner and acts as a neuromodulator. Creatine deficiency syndromes are characterized by severe mental and developmental disorders. Studies have reported that brain creatine content could be enhanced with creatine supplementation. Nevertheless, there is still limited knowledge about the effects of creatine on the central nervous system. However, ample evidence has proved the neuroprotective effects of creatine on various mental aspects, such as cognition, memory skills, and spatial memory. The present review aimed to review available experimental data and clinical observations confirming creatine roles in the central transmission process. A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, and Google Scholar database using all available MeSH terms for Creatine, Phosphocreatine, Bioenergetics, Nervous system, Brain, Cognition, and Neuroprotection. Electronic database searches were combined and duplicates were removed. Here, first, creatine and its potential influence on cognitive health and performance were briefly reviewed. Next, the existing experimental and clinical evidence was specifically explored to understand how creatine could interact as a neurotransmitter in the nervous system. Studies have revealed that exogenous creatine supplementation decreases neuronal cell loss in experimental paradigms of neurological diseases. It was observed that creatine could interact with the N-methyl-D-aspartate receptor, Na+-K+-ATPase enzyme, GABAA receptor, serotonin 1A receptors, and presumably α1-adrenoceptor and play critical roles in the central transmission process which implies that creatine can be considered a neuromodulator.
... CrP regenerates ATP at a rate 10 times faster than glycolysis and 40 times faster than mitochondrial oxidative phosphorylation, allowing muscle cells to handle sudden energy demands. On the other hand, 1 proton (H+) is released each time 1 ATP is hydrolyzed to ADP, which could cause acidosis (decreased cellular pH), but a proton will be immediately captured by the Lohmann reaction to regenerate ATP [4]. Due to the smaller size of Cr (the molecular weight of creatine is ~130 daltons), skeletal muscle cells can store up to 10 times more Cr than ATP (the molecular weight of ATP is ~507 daltons, almost 4 times higher) as an energy reserve [1,2]. ...
... Creatine phosphate is transported to the cytoplasm and is available to donate the phosphate group to ADP. homocysteine [1,4]. This seemingly simple pathway is complicated by the fact that most cells do not produce these two enzymes in equivalent amounts. ...
... It also has neuroprotective effects and positively interferes with cognition [26,27]. There is already enough empirical evidence to support that both in conditions of hypoxia and normoxia it is advantageous to use oral supplementation of Crem in healthy adults [4,8,28]. On the other hand, when Cr/CrP concentrations and CK activity are low, they are correlated with neurodegenerative diseases [29]. ...
... It is important to consume whole foods and intake all macronutrients in the diet. However, the literature shows that dietary supplements and ergogenic aids may be able to improve athletic performance [66], enhance cognitive function [67], and help meet caloric needs for males and females [68], which in turn could improve occupational performance in firefighters. In addition, it may be difficult for on-duty firefighters to have time to prepare well-balanced meals; therefore, dietary supplements may be beneficial. ...
... Particularly, creatine is beneficial for high-intensity exercise performance [87,88] as it increases phosphocreatine levels within skeletal muscle [89]. In addition, creatine has shown to be neuroprotective regarding traumatic brain injuries, aid in recovery from brain injuries [90], and helps with overall cognitive functioning [67]. Some studies suggest that creatine may help reduce the effects of sleep deprivation on cognitive function [66]. ...
Article
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The fire service suffers from high rates of cardiovascular disease and poor overall health, and firefighters often suffer fatal and non-fatal injuries while on the job. Most fatal injuries result from sudden cardiac death, while non-fatal injuries are to the musculoskeletal system. Previous works suggest a mechanistic link between several health and performance variables and injury risk. In addition, studies have suggested physical activity and nutrition can improve overall health and occupational performance. This review offers practical applications for exercise via feasible training modalities as well as nutritional recommendations that can positively impact performance on the job. Time-efficient training modalities like high-intensity interval training and feasible modalities such as resistance training offer numerous benefits for firefighters. Also, modifying and supplementing the diet and can be advantageous for health and body composition in the fire service. Firefighters have various schedules, making it difficult for planned exercise and eating while on shift. The practical training and nutritional aspects discussed in this review can be implemented on-shift to improve the overall health and performance in firefighters.
... ATP-dependent calcium transporters can counteract the calcium gradient under consumption of ATP and PCr, maintain the cell milieu, and thus normalize mitochondrial function [65,66]. Oxygen radicals can be intercepted [67]. Even transient hypoxia of a few seconds can be counteracted by the body in this way [68]. ...
... Creatine was able to protect animal brain tissues from the apoptotic effects of excitatory amino acids [213,214]. Lastly, it was shown that Creatine stabilizes mPTP in rodent studies, thus protecting brain tissue from apoptosis and cell death [67]. Table 5 presents a summary of the level of evidence related to creatine supplementation for traumatic and ischemic CNS injuries [205][206][207]. ...
Article
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Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some chronic and traumatic diseases. Creatine supplementation has been reported to improve high-energy phosphate availability as well as have antioxidative, neuroprotective, anti-lactatic, and calcium-homoeostatic effects. These characteristics may have a direct impact on mitochondrion’s survival and health particularly during stressful conditions such as ischemia and injury. This narrative review discusses current scientific evidence for use or supplemental CrM as a therapeutic agent during conditions associated with mitochondrial dysfunction. Based on this analysis, it appears that CrM supplementation may have a role in improving cellular bioenergetics in several mitochondrial dysfunction-related diseases, ischemic conditions, and injury pathology and thereby could provide therapeutic benefit in the management of these conditions. However, larger clinical trials are needed to explore these potential therapeutic applications before definitive conclusions can be drawn.
... Based on the fact that creatine use shows development in athletic and sportive performance, the effects of creatine use in athletes, sedentary, elderly individuals and some patient population is an area researched in literature (34,56,58,59). Contradictory results have been found in studies conducted on the use of creatine (2,18,31,56). ...
... Based on the fact that creatine use shows development in athletic and sportive performance, the effects of creatine use in athletes, sedentary, elderly individuals and some patient population is an area researched in literature (34,56,58,59). Contradictory results have been found in studies conducted on the use of creatine (2,18,31,56). Turner et al. (64) examined the effects of creatine supplement during acute lack of oxygen in young adults on neurophysiological and neuropsychological functions. As a result, it was found that creatine supplement increased neural creatine level and prevented attention disorders that occurred during lack of oxygen. ...
Article
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Creatine, which is a popular ergogenic aid, is shown among the most effective methods used as a performance enhancer in athletes. The aim of this review is to summarize the current publications to show the uses and effects of creatine in exercise. In the present study prepared in a systematic review style, full-text articles about creatine use published in Science Citation Index (SCI), SCI-Expanded, and PubMed/MEDLINE databases' journals between 2010 and 2021 were examined. The searching was performed by "creatine", "creatine monohydrate" and "creatine supplementation" keywords. Data from 46 studies showed that creatine loading in individuals who train during high intensity and short term exercise forms affect performance positively, develop muscle mass/strength and increase muscle creatine phosphate (PCr) stores. It was also found that creatine supplement applied with strength training in elderly individuals increased muscle mass, muscle strength, and movement capacity. It is determined that there is no definitive and clear procedure regarding the usage dosage for creatine. In addition, though some studies have reported that creatine use has a positive effect on cognitive performance, a definite judgment has not been reached. Consequently, it has been demonstrated that creatine supplementation is an effective ergogenic aid for the development of muscle and strength for athletes of all levels. The increase in the number of studies on the creatine usage dosage to be examined in different athlete profiles may lead to a decrease in the contradictions about the usage procedure.
... stress in experimental hyperglycemia [4,5], being used as a treatment in diabetic transgenic models, and resulting in a decrease of oxidative markers and protein carbonyls at the level of cytosol and brain mitochondrial fractions, with restoration of mitochondrial complex I, II and III activities [4,5]. ...
... stress in experimental hyperglycemia [4,5], being used as a treatment in diabetic transgenic models, and resulting in a decrease of oxidative markers and protein carbonyls at the level of cytosol and brain mitochondrial fractions, with restoration of mitochondrial complex I, II and III activities [4,5]. ...
... Inhibitory effects elicited in vitro and in vivo by hydrogen sulfide, thiosulfate and EMA in distinct rat brain regions were also observed on the activity of creatine kinase (CK) (Cardoso et al. 2017;de Moura Alvorcem et al. 2019;Grings et al. 2013;Grings et al. 2018;Leipnitz et al. 2003;Rae and Broer 2015;Schuck et al. 2002;Sumien et al. 2018), another enzyme crucial for cellular energy homeostasis in central nervous system (Rae and Broer 2015;Sumien et al. 2018). This enzyme catalyzes the reversible reaction of creatine with ATP to produce phosphocreatine and ADP, playing a key role in the energy transfer from the sites of ATP production in mitochondria to the cytosol, as well as in energy buffering (Sumien et al. 2018). ...
... Inhibitory effects elicited in vitro and in vivo by hydrogen sulfide, thiosulfate and EMA in distinct rat brain regions were also observed on the activity of creatine kinase (CK) (Cardoso et al. 2017;de Moura Alvorcem et al. 2019;Grings et al. 2013;Grings et al. 2018;Leipnitz et al. 2003;Rae and Broer 2015;Schuck et al. 2002;Sumien et al. 2018), another enzyme crucial for cellular energy homeostasis in central nervous system (Rae and Broer 2015;Sumien et al. 2018). This enzyme catalyzes the reversible reaction of creatine with ATP to produce phosphocreatine and ADP, playing a key role in the energy transfer from the sites of ATP production in mitochondria to the cytosol, as well as in energy buffering (Sumien et al. 2018). ...
Article
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Ethylmalonic encephalopathy (EE) is a severe intoxication disorder caused by mutations in the ETHE1 gene that encodes a mitochondrial sulfur dioxygenase involved in the catabolism of hydrogen sulfide. It is biochemically characterized by tissue accumulation of hydrogen sulfide and its by-product thiosulfate, as well as of ethylmalonic acid due to hydrogen sulfide-induced inhibition of short-chain acyl-CoA dehydrogenase. Patients usually present with early onset severe brain damage associated to encephalopathy, chronic hemorrhagic diarrhea and vascular lesions with petechial purpura and orthostatic acrocyanosis whose pathophysiology is poorly known. Current treatment aims to reduce hydrogen sulfide accumulation, but does not significantly prevent encephalopathy and most fatalities. In this review, we will summarize the present knowledge obtained from human and animal studies showing that disruption of mitochondrial and redox homeostasis may represent relevant pathomechanisms of tissue damage in EE. Mounting evidence show that hydrogen sulfide and ethylmalonic acid markedly disturb critical mitochondrial functions and induce oxidative stress. Novel therapeutic strategies using promising candidate drugs for this devastating disease are also discussed.
... 3 due to the relationship between mental fatigue and neuronal bioenergetics, changes in brain pcr may therefore have significant effects on cognitive function. 4 creatine monohydrate supplementation (crS) has been reported to increase creatine content in the human brain. 4 although brain saturation is minimal compared to skeletal muscle following similar dosing protocols, crS may nonetheless significantly augment neuronal pcr and subsequently provide a temporal energy buffer to resist mental fatigue. ...
... 4 although brain saturation is minimal compared to skeletal muscle following similar dosing protocols, crS may nonetheless significantly augment neuronal pcr and subsequently provide a temporal energy buffer to resist mental fatigue. 4 Therefore, we tested the effects of crS on cognitive performance immediately after a mountain bike time trial located on a competitive track. We hypothesized that a 7-day creatine loading supplementation protocol would postpone the onset of mental fatigue and prevent decreased cognitive performance. ...
Article
Supplemental creatine monohydrate loading improves cognitive function in experienced mountain bikers Mountain bikers need to perform in a dynamically changing, high-paced environment. These athletes are subject to tracks with wide ranging climbs and descents (ex. boardwalks, berms, large rocks, medium steps, drop-offs, cambers and water crossings) ...
... Brain creatine deficiency is associated with major mental developmental disorders, and supplementation may alleviate these problems. Creatine aids recovery as a neuroprotective agent from the chronic manifestations that lead to oxidative stress and cognitive function post-brain injury [109][110][111]. ...
Article
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Traumatic brain injury (TBI) represents a multifaceted pathological condition resulting from external forces that disrupt neuronal integrity and function. This narrative review explores the intricate relationship between dietary macronutrients, gut microbiota (GM), and neuroinflammation in the TBI. We delineate the dual aspects of TBI: the immediate mechanical damage (primary injury) and the subsequent biological processes (secondary injury) that exacerbate neuronal damage. Dysregulation of the gut–brain axis emerges as a critical factor in the neuroinflammatory response, emphasizing the role of the GM in mediating immune responses. Recent evidence indicates that specific macronutrients, including lipids, proteins, and probiotics, can influence microbiota composition and in turn modulate neuroinflammation. Moreover, specialized dietary interventions may promote resilience against secondary insults and support neurological recovery post-TBI. This review aims to synthesize the current preclinical and clinical evidence on the potential of dietary strategies in mitigating neuroinflammatory pathways, suggesting that targeted nutrition and gut health optimization could serve as promising therapeutic modalities in TBI management.
... Creatine, as a nutrient essential for maintaining energy homeostasis in the cells across the body, including in the brain [6,7], is a promising candidate for interventions in ME/CFS [8][9][10]. The primary role of creatine is as an acceptor of high-energy phosphate in a reaction catalysed by creatine kinase that creates phosphocreatine (creatine + ATP <-> PCr + ADP + H + ; ATP-adenosine triphosphate, ADP-adenosine diphosphate, PCrphosphocreatine). Phosphocreatine acts as an energy buffer, quickly and easily diffusing to sites of demand to regenerate ATP [11]. As such, creatine availability is critical for energy-demanding tissues such as brain and muscle. ...
Article
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Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic medical condition with no specific pharmacological treatment. Creatine, a nutrient essential for maintaining energy homeostasis in the cells, is a candidate for interventions in ME/CFS. Methods: Fourteen participants with ME/CFS received supplementation with 16 g creatine monohydrate for 6 weeks. Before starting creatine and on the last day of treatment, participants underwent brain magnetic resonance spectroscopy (MRS) scanning of the pregenual anterior cingulate cortex (pgACC) and dorsolateral prefrontal cortex (DLPFC), followed by symptom, cognition, and hand-grip strength assessments. Results: Eleven participants completed the study. Creatine treatment increased creatine concentration in both the pgACC and DLPFC (p = 0.004 and 0.012, respectively), decreased fatigue and reaction time (RT) on congruent and incongruent trials of the Stroop test (p = 0.036 and 0.014, respectively), and increased hand-grip strength (p = 0.0004). There was a positive correlation between increases in pgACC creatine and changes in RT on Stroop congruent and incongruent trials (p = 0.048 and p = 0.022, respectively). Creatine was well tolerated, and none of the participants stopped treatment. Conclusion: Creatine supplementation over six weeks in ME/CFS patients increased brain creatine and improved fatigue and some aspects of cognition. Despite its methodological limitations, this study encourages placebo-controlled investigations of creatine treatment in ME/CFS.
... Dietary creatinine in-take can raise brain creatine and preserve the brain's cognitive function under stress. Consumption of creatinine is assessed in several adult neuro-degenerative conditions since it directly preserves mitochondrial function [181]. ...
Article
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Purpose The objective of the present study was to provide an update on the 16 sports with the highest incidence of brain injuries. Thereafter, its diagnosis, treatment, and management strategies are discussed. Methods The manuscript addresses the brain-related injuries individually in each of the 16 sports with the highest incidence. To simplify the reading, the mentioned 16 sports are sorted alphabetically. A subpart mentioning the management of brainrelated sports injuries, including pharmacological management, is also included in the manuscript. Results The incidence of sports-mediated brain injuries within hospital-based studies ranged between 3.5 and 31.5 per 100,000. One community-based study using multiple case ascertainment sources identified a higher incidence of 170 per 100,000. Brain injuries due to sports total 1.2–30.3% of all TBIs (traumatic brain injuries). Men have a higher prevalence than women (75.6% vs. 66.1%), and adolescents and young adults had the highest incidence of sports-mediated brain injuries. Almost 50% of head injuries reported during the practice of sports or recreational activities occur in bicycling, skateboarding, or skating incidents. More than 775,000 children, aged 14 and younger, are treated yearly in hospital emergency rooms for sports-related injuries. Conclusions Brain injuries are common in sports and difficult to manage, but athlete health and injury prevention should be the priority. Preventive measures should be stricter in sports with a higher incidence of brain injury. As for treatment, a comprehensive approach should be adopted.
... Entre los estudios más recientes que han reportado beneficios asociados a la suplementación con Cr, el uso diario de 20 g del suplemento ha demostrado aumentar la capacidad cognitiva en deportistas vegetarianos (Borchio, 2020). También en adultos vegetarianos, el uso de 5 g de Cr durante seis semanas se asoció con una mejora en dos tests cognitivos (Rae, 2015). En adultos ICU ISSN 2525ISSN -1783 Año 2023 / Vol 7 -Nº 8 http://revistas.umaza.edu.ar/index.php/icu/index ...
Article
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La creatina es el suplemento deportivo más popular por su contribución al rendimiento deportivo y al mejoramiento de la composición corporal. Debido a que cumple funciones no solo a nivel muscular, sino en todos los tejidos del cuerpo, especialmente en el sistema nervioso, su interés como ayuda en diversas condiciones de salud y enfermedad ha crecido en las últimas décadas. Sin embargo, muchas de las investigaciones han sido realizadas en animales, en modelos que no representan tan adecuadamente las realidades del ser humano, en quienes la creatina mejoraría características de la función cognitiva principalmente. En la presente revisión narrativa se detallan los hallazgos más importantes de investigaciones recientes efectuadas en seres humanos en la última década, tendientes a analizar el beneficio de la creatina en funciones cognitivas, depresión, daño al sistema nervioso central, enfermedades neurodegenerativas, salud cardiovascular y otras condiciones relevantes. Además, se discute el concepto de seguridad en su dosificación, incluyendo los resultados de estudios individuales, revisiones y metaanálisis recientes.
... A supplementation with creatine doubled the cellular contents of CrP and the CrP/ATP ratio in astrocytes which may improve the ability of these cells to temporarily deal with situations of compromised metabolic ATP regeneration. Further studies are now required to elucidate beneficial consequences of a treatment of astrocytes with creatine and whether such processes may contribute to the wide range of reported health and therapeutical beneficial effects of a creatine supplementation [70][71][72][73][74]. ...
Article
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Adenosine triphosphate (ATP) is the main energy currency of all cells, while creatine phosphate (CrP) is considered as a buffer of high energy-bond phosphate that facilitates rapid regeneration of ATP from adenosine diphosphate (ADP). Astrocyte-rich primary cultures contain ATP, ADP and adenosine monophosphate (AMP) in average specific contents of 36.0 ± 6.4 nmol/mg, 2.9 ± 2.1 nmol/mg and 1.7 ± 2.1 nmol/mg, respectively, which establish an adenylate energy charge of 0.92 ± 0.04. The average specific cellular CrP level was found to be 25.9 ± 10.8 nmol/mg and the CrP/ATP ratio was 0.74 ± 0.28. The specific cellular CrP content, but not the ATP content, declined with the age of the culture. Absence of fetal calf serum for 24 h caused a partial loss in the cellular contents of both CrP and ATP, while application of creatine for 24 h doubled the cellular CrP content and the CrP/ATP ratio, but did not affect ATP levels. In glucose-deprived astrocytes, the high cellular ATP and CrP contents were rapidly depleted within minutes after application of the glycolysis inhibitor 2-deoxyglucose and the respiratory chain inhibitor antimycin A. For those conditions, the decline in CrP levels always preceded that of ATP contents. In contrast, incubation of glucose-fed astrocytes for up to 30 min with antimycin A had little effect on the high cellular ATP content, while the CrP level was significantly lowered. These data demonstrate the importance of cellular CrP for maintaining a high cellular ATP content in astrocytes during episodes of impaired ATP regeneration.
... Benzer şekilde yapılan diğer çalışmalar incelendiğinde, sporcularda kreatin alımının bilişsel fonksiyonlar üzerindeki olumlu etkisine dair kanıtlar çelişkili veya sadece orta düzeyde etkili görülmektedir. 62,66 Dolayısıyla bilişsel fonksiyonun gelişimi ve mental yorgunlukla başa çıkmada kreatinin potansiyel rolü konusunda daha fazla araştırmaya ihtiyaç duyulmaktadır. ...
... Accordingly, mitochondrial dysfunction could lead to hepatocyte cell death and/or apoptosis [23], which is intensely associated with MAFLD [24]. These oxidative stresses including oxygen radicals could be seized [25]. Indeed, this highlights the importance of healthy mitochondria for the maintenance of healthy hepatocyte functions. ...
Article
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Mitophagy/autophagy plays a protective role in various forms of liver damage, by renovating cellular metabolism linking to sustain liver homeostasis. A characterized pathway for mitophagy is the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin-dependent signaling pathway. In particular, PINK1-mediated mitophagy could play an indispensable role in improving the metabolic dysfunction-associated fatty liver disease (MAFLD) which could precede to steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. In addition, the PI3K/AKT/mTOR pathway might regulate the various characteristics of cellular homeostasis including energy metabolism, cell proliferation, and/or cell protection. Therefore, targeting mitophagy with the alteration of PI3K/AKT/mTOR or PINK1/Parkin-dependent signaling to eliminate impaired mitochondria might be an attractive strategy for the treatment of MAFLD. In particular, the efficacy of prebiotics for the treatment of MAFLD has been suggested to be useful via the modulation of the PI3K/AKT/mTOR/AMPK pathway. Additionally, several edible phytochemicals could activate mitophagy for the improvement of mitochondrial damages, which could also be a promising option to treat MAFLD with providing liver protection. Here, the potential therapeutics with several phytochemicals has been discussed for the treatment of MAFLD. Tactics with a viewpoint of prospective probiotics might contribute to the development of therapeutic interventions.
... Creatine kinase (CK), the main enzyme involved in the ATP/creatine phosphate (CrP) system, is also expressed in a brain-specific isoform (BB-CK), suggesting that creatine may also be relevant for energy provision to the central nervous system (CNS) (Dolan et al., 2019;Rackayova et al., 2017;Riesberg et al., 2016;Roschel et al., 2021). Cognitive processing may also be affected by creatine metabolism, as it may facilitate ATP homeostasis during periods of rapid or altered brain ATP turnover, such as during complex cognitive tasks, hypoxia, sleep deprivation, and some neurological conditions (Dolan et al., 2019;Gerbatin et al., 2019;Rae & Bröer, 2015;Riesberg et al., 2016). The brain can synthesise creatine and does not appear to rely on endogenous production from other organs or exogenous dietary sources (Dolan et al., 2019). ...
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Aims: The purpose was to examine the relationship between dietary creatine intake obtained in food and selective attention and inhibitory control processes in older adults. Methods: Forty-five (n = 11 males; n = 34 females) participants over 60 years of age volunteered. Participants completed a 5-day dietary recall survey to estimate creatine intake and a cognitive assessment which included an adaptation of the Eriksen flanker task and a mini-mental state examination (MMSE). Cohorts for two groups were derived based on higher (HCr) versus lower (LCr) median creatine intake. To compare the groups, an unpaired Mann-Whitney U test was performed. In addition, Spearman’s correlation analysis was used to test a potential association between the daily amount of creatine with selective attention and inhibitory processing task results. Results: There were significant differences between the groups in the flanker task. In the incongruent condition, HCr responded on average about 646 ms faster than LCr (p = .005). HCr also responded about 25% more accurately than LCr in the incongruent condition (p < .001). Response time to incongruent stimuli (Spearman’s -0.424) and per cent correct (Spearman’s rho 0.565) showed moderate correlations with daily creatine intake. Conclusions: Creatine intake from food is positively associated with selective attention and inhibitory processing in older adults.
... Complex cognitive tasks, hypoxia, sleep deprivation, and some neurological conditions are characterized by rapid brain metabolic activity and ATP depletion, where creatine metabolism could be essential for energy homeostasis (21)(22)(23)(24). It is important to highlight that the brain creatine content may also decrease with age, and age-related decreases in brain creatine content could be associated with reduced brain activity or disease (22,25). ...
Article
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Creatine (Cr) has been proposed as an ergogenic resource and the adhesion to its therapeutic use has gained relevance in the last 2 decades. The role of Cr in the aging process has been highlighted, with many studies aiming to understand how aging affects the depletion of Cr resources in muscle and brain, especially because Cr is a natural regulator of energy homeostasis and plays a recognized role in brain function and development, justifying the rising hypothesis that Cr supplementation can help mitigate the effects of aging. Thus, we aimed to review the role of Cr (supplemented or obtained in daily diet) and its metabolism in the aging brain, with emphasis on cognition/memory. PubMed, PsychInfo, EBSCO, Medline, BioMed central and Science Direct, constituted the searched databases. Inclusion criteria specified peer-reviewed studies investigating creatine metabolism and/or creatine supplementation, and assessing cognition, and memory in old adults, and published between January, 2000 to September, 2022. The importance of creatine in the brain’s energy metabolism is well established. The relationship between the decline of cognitive function and brain creatine storage still lacks stronger evidence. Evidence is also lacking on whether creatine supplementation is beneficial in mitigating the neural effects of aging, remaining an open field of studies that brings optimistic perspectives.
... Cr is known to have effects other than an energy source, and Cr supplement has been thought to be beneficial for children, pregnant and lactating women, and old people 79,249 . Cr has been reported to improve human mental performance [250][251][252][253][254][255] . Cr has been used as potential treatment in animal models of neurodegenerative diseases 256,257 . ...
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It has never been easy to discover a new neurotransmitter, especially one in the central nervous system (CNS). We have been searching for new neurotransmitters for 12 years. We detected creatine (Cr) in synaptic vesicles (SVs), at a level lower than glutamate (Glu) and gamma-aminobutyric acid (GABA) but higher than acetylcholine (ACh) and 5-hydroxytryptamine (5-HT). SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (AGAT, a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability (ID) in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in SLC6A8 and AGAT mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP dependent manner. Thus, our biochemical, chemical, genetic and electrophysiological results suggest Cr as a neurotransmitter, illustrate a novel approach to discover neurotransmitters and provide a new basis for ID pathogenesis.
... Accordingly, mitochondrial dysfunction could also lead to neuronal cell death and/or apoptosis [12], which is associated with neurological complications, including Alzheimer's disease, Parkinson's disease, and Huntington's disease [13]. These oxidative stresses that include oxygen radicals could be intercepted [14]. In various neurodegenerative diseases such as ALS, several defects in mitochondrial function leading to oxidative stresses have been identified in underlying relations [15]. ...
Article
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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, the pathogenesis of which is based on alternations in the mitochondria of motor neurons, causing their progressive death. A growing body of evidence shows that more efficient mitophagy could prevent and/or treat this disorder by suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. Mitophagy has been considered one of the main mechanisms responsible for mitochondrial quality control. Since ALS is characterized by enormous oxidative stress, several edible phytochemicals that can activate mitophagy to remove damaged mitochondria could be considered a promising option to treat ALS by providing neuroprotection. Therefore, it is of great significance to explore the mechanisms of mitophagy in ALS and to understand the effects and/or molecular mechanisms of phytochemical action, which could translate into a treatment for neurodegenerative diseases, including ALS.
... Creatine is an endogenous compound that is predominantly stored in skeletal muscles but is also present in other parts of the body, such as the liver, kidneys, or brain [168,169]. The predominant role of creatine is to maintain energy homeostasis by keeping ATP levels constant in cells with high energy demands, such as neurons [170]. In addition, this endogenous compound can also reduce free radical formation and promote the restoration of Ca 2+ homeostasis by decreasing both intracellular and mitochondrial Ca 2+ levels [168,171]. ...
Article
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Pesticides of different chemical classes exert their toxic effects on the nervous system by acting on the different regulatory mechanisms of calcium (Ca2+) homeostasis. Pesticides have been shown to alter Ca2+ homeostasis, mainly by increasing its intracellular concentration above physiological levels. The pesticide-induced Ca2+ overload occurs through two main mechanisms: the entry of Ca2+ from the extracellular medium through the different types of Ca2+ channels present in the plasma membrane or its release into the cytoplasm from intracellular stocks, mainly from the endoplasmic reticulum. It has also been observed that intracellular increases in the Ca2+ concentrations are maintained over time, because pesticides inhibit the enzymes involved in reducing its levels. Thus, the alteration of Ca2+ levels can lead to the activation of various signaling pathways that generate oxidative stress, neuroinflammation and, finally, neuronal death. In this review, we also discuss some proposed strategies to counteract the detrimental effects of pesticides on Ca2+ homeostasis.
... I could not fail to mention briefly, in order not to escape the subject, that studies show effects of creatine supplementation on bone health and cognition in elderly people [6]. Increased memory retention, reaction time and intelligence tests' results have been observed by several researchers around the world [7][8][9]. The findings indirectly affect the reduction of frailty and the risk of falls, in addition to contributing to the quality of life of the elderly. ...
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To the editor, Recently Tong Ji et al [1] published a work of great importance for public health. The problems associated with aging will increase over the next 3 decades following the growth rate in the age group above 60 years old (wich will be about 21% in 2050). One of these problems is sarcopenic obesity (SO) which is a loss of muscle mass, strength and increase in body fat. SO cause frailty, falls, disability, immobility, fractures, cardiometabolic and respiratory diseases, cancer, and increased mortality. After showing the different methodologies for diagnosis and the physiological mechanisms of SO, Tong Ji et al [1] discuss intervention and treatment proposals such as physical exercise and dietary intervention strategies, as would be expected in the topic. However, I would like to add contribution to the excellent work of the authors. Among the nutritional strategies against SO in the elderly, creatine supplementation has been proposed as the most effective when associated with physical exercise [2-4]. Chilibeck et al [4] show in a meta-analysis (22 studies; n=722s) significant gain in lean mass (mean difference =1.44 [95% CI =1.02-1.86] kg; p<0.00001) among people aged 57 to 70 years supplemented with creatine plus exercise compared to placebo. Additionally, they showed that creatine supplementation increases strength in upper and lower limbs. About frailty and risk of falls, Candow et al [6] showed that elderly individuals performing resistance exercises plus creatine supplementation improved the efficiency in the sit-to-stand test by 23%, while those who performed only the exercise improved by 16%. The sit-and-stand test is recognized as one of the best tests to assess the risk of falls. Devries & Phillips [5] showed that creatine supplementation, as compared with placebo, during RT significantly increased the number of chair stands completed in 30 s (weighted mean difference, 1.93 stands; 95% CI, 0.19 to 3.67 stands; P = 0.03, ES, 1.19). These meta-analyses strengthen the empirical evidence for the adoption of creatine supplementation as an enhancer of the functional capacity of the elderly in facing frailty and the risk of falls. Creatine supplementation contributes to combat SO through several mechanisms, the increase in the intramuscular CrP concentration (with strong empirical evidence) allows more efficiency during exercise, enhancing its effects [3]. Other mechanisms still lack more empirical evidence but seem to involve endocrine, immunological and biomolecular factors (activation of the AKT-mTOR pathway and inhibition of myostatin)[3,4]. I could not fail to mention briefly, in order not to escape the subject, that studies show effects of creatine supplementation on bone health and cognition in elderly people [6]. Increased memory retention, reaction time and intelligence tests' results have been observed by several researchers around the world [7-9]. The findings indirectly affect the reduction of frailty and the risk of falls, in addition to contributing to the quality of life of the elderly. Last but not least is to highlight the accumulation of evidence that creatine supplementation is safe for the
... Creatine acts as an antioxidant and improves mitochondrial function [418]. Although a pilot study reported in 2006 could not detect any improvement in the UPDRS scores of PD patients after 2-4 g creatine/day for 2 years [419], a subsequent phase 2 multi-center, doubleblind, pilot study of minocycline and creatine was conducted in 195 patients with early untreated PD to test efficacy in slowing disease progression (National Institute for Neurological Disorders and Stroke Parkinson's Disease Neuroprotection Trial, NCT00063193) and showed promising results [420], followed by a larger phase 3 double-blind, parallel-group, placebo controlled study (NET-PD LS-1, NCT00449865), which enrolled 1741 participants who were administered 10 creatine/day for 5 years, which failed to show improvements in clinical outcome [421]. ...
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As the population ages, the incidence of neurodegenerative diseases is increasing. Due to intensive research, important steps in the elucidation of pathogenetic cascades have been made and significantly implicated mitochondrial dysfunction and oxidative stress. However, the available treatment in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis is mainly symptomatic, providing minor benefits and, at most, slowing down the progression of the disease. Although in preclinical setting, drugs targeting mitochondrial dysfunction and oxidative stress yielded encouraging results, clinical trials failed or had inconclusive results. It is likely that by the time of clinical diagnosis, the pathogenetic cascades are full-blown and significant numbers of neurons have already degenerated, making it impossible for mitochondria-targeted or antioxidant molecules to stop or reverse the process. Until further research will provide more efficient molecules, a healthy lifestyle, with plenty of dietary antioxidants and avoidance of exogenous oxidants may postpone the onset of neurodegeneration, while familial cases may benefit from genetic testing and aggressive therapy started in the preclinical stage.
... It is believed that aging is associated with a reduction in creatine levels in brain tissues [9]. In addition, the dietary supplementation of GA or creatine is vital for maintaining the concentration of creatine in brain tissues, even when the pathway of creatine synthesis in brain is efficient [10]. Based on animal model trials, supplements of creatine or its precursors may be an effective defense mechanism against some neuromuscular [11] and neurodegenerative disorders [12]. ...
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Guanidinoacetic acid (GA) is a natural precursor of creatine in the body and is usually used to improve the feed conversion and cellular energy metabolism of broiler chickens. The objective was to elucidate the effect of dietary supplementation of GA on carcass yield, muscle amino acid profile, and concentrations of brain neurotransmitters in laying hens. In total, 128 72-week-old ISA Brown laying hens were assigned to four equal groups (32 birds, eight replicates per group). The control group (T1) was fed a basal diet with no supplements, while the other experimental groups were fed a basal diet supplemented with 0.5 (T2), 1.0 (T3), and 1.5 (T4) g GA kg−1 diet. The T3 and T4 groups showed higher hen-day egg production and carcass yield compared to the control group (p = 0.016 and 0.039, respectively). The serum creatine level increased linearly with the increased level of dietary GA (p = 0.007). Among the essential amino acids of breast muscle, a GA-supplemented diet linearly increased the levels of leucine, isoleucine, phenylalanine, methionine, and threonine in the breast (p = 0.003, 0.047, 0.001, 0.001, and 0.015, respectively) and thigh (p = 0.026, 0.001, 0.020, 0.009, and 0.028, respectively) muscles. GA supplementation linearly reduced the level of brain serotonin compared to the control group (p = 0.010). Furthermore, supplementation of GA in the diet of laying hens linearly increased the level of brain dopamine (p = 0.011), but reduced the level of brain Gamma-aminobutyric acid (p = 0.027). Meanwhile, the concentration of brain nitric oxide did not differ between the experimental groups (p = 0.080). In conclusion, the dietary supplementation of GA may improve the carcass yield and levels of essential amino acids in the breast muscles, as well as the brain neurotransmitters in aged laying hens.
... Creatine levels are directly related to brain function and ATP turnover (Rae & Broer, 2015) through creatine kinase systems located in both the cytosol and mitochondrion. Increased creatine levels are known to relate to improved cognitive function (Avgerinos, Spyrou, Bougioukas, & Kapogiannis, 2018) and supplementation has been suggested to decrease mental fatigue (Watanabe, Kato, & Kato, 2002). ...
Article
It is challenging to determine which patients with obstructive sleep apnea (OSA) have impaired driving ability. Vulnerability to this neurobehavioral impairment may be explained by lower brain metabolites levels involved in mitochondrial metabolism. This study compared markers of brain energy metabolism in OSA patients identified as vulnerable vs resistant to driving impairment following extended wakefulness. 44 patients with moderate-severe OSA underwent 28hr extended wakefulness with three 90min driving simulation assessments. Using a two-step cluster analysis, objective driving data (steering deviation and crashes) from the 2nd driving assessment (22.5 h awake) was used to categorise patients into vulnerable (poor driving, n = 21) or resistant groups (good driving, n = 23). 1 H magnetic resonance spectra were acquired at baseline using two scan sequences (short echo PRESS and longer echo-time asym-metric PRESS), focusing on key metabolites, creatine, glutamate, N-acetylaspartate (NAA) in the hippocampus, anterior cingulate cortex and left orbito-frontal cortex. Based on cluster analysis, the vulnerable group had impaired driving performance compared with the resistant group and had lower levels of creatine (PRESS p = ns, APRESS p = 0.039), glutamate, (PRESS p < 0.01, APRESS p < 0.01), NAA (PRESS p = 0.038, APRESS p = 0.035) exclusively in the left orbito-frontal cortex. Adjusted analysis, higher glutamate was associated with a 21% (PRESS) and 36% (APRESS) reduced risk of vulnerable classification. Brain mitochondrial bioenergetics in the frontal brain regions are impaired in OSA patients who are vulnerable to driving impairment following sleep loss. These findings provide a potential way to identify at risk OSA
... Thus, D IRS2 −/− mice presented low levels of ATP and creatine, whereas ND IRS2 −/− mice showed values comparable to WT mice, suggesting an adequate energy status. Creatine plays a key role as buffering energy supply in tissues with high-energy demand, such as the brain [25]. However, both D and ND IRS2 −/− mice have extremely low levels of NAD. ...
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Insulin receptor substrate (IRS) 2 is a key mediator of insulin signaling and IRS-2 knockout (IRS2−/−) mice are a preclinical model to study the development of diabetes, as they develop peripheral insulin resistance and beta-cell failure. The differential inflammatory profile and insulin signaling in the hypothalamus of non-diabetic (ND) and diabetic (D) IRS2−/− mice might be implicated in the onset of diabetes. Because the lipid profile is related to changes in inflammation and insulin sensitivity, we analyzed whether ND IRS2−/− mice presented a different hypothalamic fatty acid metabolism and lipid pattern than D IRS2−/− mice and the relationship with inflammation and markers of insulin sensitivity. ND IRS2−/− mice showed elevated hypothalamic anti-inflammatory cytokines, while D IRS2−/− mice displayed a proinflammatory profile. The increased activity of enzymes related to the pentose-phosphate route and lipid anabolism and elevated polyunsaturated fatty acid levels were found in the hypothalamus of ND IRS2−/− mice. Conversely, D IRS2−/− mice have no changes in fatty acid composition, but hypothalamic energy balance and markers related to anti-inflammatory and insulin-sensitizing properties were reduced. The data suggest that the concurrence of an anti-inflammatory profile, increased insulin sensitivity and polyunsaturated fatty acids content in the hypothalamus may slow down or delay the onset of diabetes.
... Violin plots in E, G, and H are representative of 3 independent experiments, with n = 3-7 (E) or 3 (G and H) biological replicates; all other data are shown as mean ± SEM. Statistical significance was determined using Student's t test (B and D), 1-way ANOVA followed by Tukey's multiple comparisons post hoc test (E), or 2-way ANOVA followed by Tukey's multiple comparisons post hoc test (G and H) is hydrolyzed to ADP, which would have lowered the cellular pH, but the proton is promptly recycled by Cr/ PCr to regenerate ATP (33). Third, due to the smaller size of Cr, skeletal muscle cells store up to 10-fold more Cr than ATP as the energy reserve (1). ...
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Creatine transporter (CrT) upholds the brain creatine (Cr) levels, but the impacts of its deficiency on energetics adaptation under stress remain unclear. There are also no effective treatments of CrT-deficiency, the second most common cause of X-linked intellectual disabilities. Herein we examined the consequences of CrT-deficiency in brain energetics and stress-adaptation responses plus the effects of intranasal Cr supplement. We found that CrT-deficient (CrT-/y) mice harbored dendritic spine and synaptic dysgenesis. Nurtured newborn CrT-/y mice maintained the baseline brain ATP level with a tendency towards the pAMPK/autophagy from mTOR signaling activity. Starvation elevated the signaling imbalance and reduced the brain ATP level in P3 CrT-/y mice. Similarly, CrT-/y neurons and P10 CrT-/y mice showed an imbalance between autophagy/mTOR signaling pathways and greater susceptibility to cerebral hypoxia-ischemia and ischemic insults. Notably, intranasal administration of Cr after cerebral ischemia increased the brain Cr/NAA (N-acetylaspartate) ratio, partially averted the signaling imbalance, and reduced the infarct size more potently than intraperitoneal Cr injection. These findings suggest important functions of CrT and Cr in preserving the homeostasis of brain energetics in stress conditions. Moreover, intranasal Cr supplement may be an effective treatment of congenital CrT-deficiency and acute brain injury.
... This highlights the importance of the anticipation of needs (such as the timely provision of energy and adequate environmental conditions) for the functional and structural stability of cells through adaptive changes [54]. Although efforts have been made to integrate the different points of metabolic regulation to explain the positive Nutrients 2021, 13, 2521 3 of 25 effects of CrM supplementation on physical performance [55][56][57] and health or therapeutic benefits [58][59][60], no systems biology analysis has been performed to date. Readers are encouraged to refer to the comprehensive reviews in the Special Issue on "Creatine Supplementation for Health and Clinical Diseases" to learn more about the effects of CrM supplementation [9]. ...
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Creatine (Cr) and phosphocreatine (PCr) are physiologically essential molecules for life, given they serve as rapid and localized support of energy- and mechanical-dependent processes. This evolutionary advantage is based on the action of creatine kinase (CK) isozymes that connect places of ATP synthesis with sites of ATP consumption (the CK/PCr system). Supplementation with creatine monohydrate (CrM) can enhance this system, resulting in well-known ergogenic effects and potential health or therapeutic benefits. In spite of our vast knowledge about these molecules, no integrative analysis of molecular mechanisms under a systems biology approach has been performed to date; thus, we aimed to perform for the first time a convergent functional genomics analysis to identify biological regulators mediating the effects of Cr supplementation in health and disease. A total of 35 differentially expressed genes were analyzed. We identified top-ranked pathways and biological processes mediating the effects of Cr supplementation. The impact of CrM on miRNAs merits more research. We also cautiously suggest two dose–response functional pathways (kinase- and ubiquitin-driven) for the regulation of the Cr uptake. Our functional enrichment analysis, the knowledge-based pathway reconstruction, and the identification of hub nodes provide meaningful information for future studies. This work contributes to a better understanding of the well-reported benefits of Cr in sports and its potential in health and disease conditions, although further clinical research is needed to validate the proposed mechanisms.
... When used in athletes, dietary supplementation of creatine has been suggested to improve cognitive performance (90,91), alleviate mental fatigue (91,92), attenuate effects of sleep deprivation (90,93), and improve memory (94). Many studies report an improvement in cognitive processing following creatine supplementation, but these studies are difficult to compare because of the differences in subject population, supplementation protocols, and cognitive outcomes measured (95)(96)(97). Also, attempts to translate "improved cognitive processing" to athletes and athletic performance are few. ...
Article
Creatine is a popular and widely used ergogenic dietary supplement among athletes, for which studies have consistently shown increased lean muscle mass and exercise capacity when used with short-duration, high-intensity exercise. In addition to strength gains, research has shown that creatine supplementation may provide additional benefits including enhanced postexercise recovery, injury prevention, rehabilitation, as well as a number of potential neurologic benefits that may be relevant to sports. Studies show that short- and long-term supplementation is safe and well tolerated in healthy individuals and in a number of patient populations.
... Interestingly, the present study used a low dose of creatine (3 g/day) over 28 days whereas most other studies used a higher dose (20 g/day) (Roschel et al., 2021). In support of our findings, Ling et al. (2009) and Rae and Broer (2015) both found improvements in cognitive function using a lower dose of creatine (5 g/day over 15 days and 6 weeks, respectively). Future research examining the dose response relationship with brain creatine levels and cognitive function are urgently needed, however, our research suggests that a low dose of creatine provided over 28 days appears to alter cognitive performance following exhaustive exercise. ...
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BACKGROUND: Creatine supplementation has some beneficial effects on cognitive processing in healthy adults, including athletes; however the effects on cognitive function following exhaustive exercise in athletes is unknown. Therefore, the purpose was to determine the effects of 28 days of creatine supplementation on tasks of cognitive performance immediately following exhaustive exercise in Muay Thai female athletes compared to placebo. METHODS: Using a repeated measures, double-blind, placebo controlled design, 26 female Muay Thai athletes (age: 26 ± 5 years; body mass: 65.1 ± 6.6 kg; height: 162 ± 5 cm; training experience: 2.6 ± 0.6 years) were randomized to supplement with creatine monohydrate (3 g/day) or placebo (maltodextrin) for 28 days. Prior to and following supplementation, measures of cognitive performance were assessed (visual and auditory reaction time, corsi block test, visual forward digit span, and Erikson Flanker Task) immediately after exercise. RESULTS: There was a time main effect for auditory reaction time (p = 0.035), with no differences between groups. There was a trend for an interaction effect for visual reaction time (p = 0.067), visual go-no-go reaction time (p = 0.087), and Erikson Flanker task (p = 0.06), with exploratory post hoc tests revealing improvements over time in the creatine group (p < 0.05) with no changes in the PLA group (p > 0.05). CONCLUSION: Twenty-eight days of creatine supplementation appeared to have a small but positive effect on cognitive performance following exhaustive exercise in female Muay Thai athletes. Future research using a larger dose over a longer duration is warranted.
... Additionally, creatine supplementation might be beneficial for mild traumatic brain injury (mTBI), which is also associated with changes in brain energy needs. The effects of creatine supplementation on brain creatine levels, cognitive processing, and mTBI have been previously reviewed [3,17,18]. As this is a growing field, the purpose of this short review is to provide an update regarding the effects of creatine supplementation on brain health in humans beyond what is discussed in Dolan et al. [3]. ...
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There is a robust and compelling body of evidence supporting the ergogenic and therapeutic role of creatine supplementation in muscle. Beyond these well-described effects and mechanisms, there is literature to suggest that creatine may also be beneficial to brain health (e.g., cognitive processing, brain function, and recovery from trauma). This is a growing field of research, and the purpose of this short review is to provide an update on the effects of creatine supplementation on brain health in humans. There is a potential for creatine supplementation to improve cognitive processing, especially in conditions characterized by brain creatine deficits, which could be induced by acute stressors (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g., creatine synthesis enzyme deficiencies, mild traumatic brain injury, aging, Alzheimer’s disease, depression). Despite this, the optimal creatine protocol able to increase brain creatine levels is still to be determined. Similarly, supplementation studies concomitantly assessing brain creatine and cognitive function are needed. Collectively, data available are promising and future research in the area is warranted.
... SLC6A8 encodes the creatine transporter-1 (CRT1, Nash et al., 1994;Dai, Vinnakota, Qian, Kunze, & Sarkar, 1999). Creatine, a precursor of phosphocreatine, acts as an energy buffer to maintain cellular ATP levels (Rae & Bröer, 2015). Over 80 point mutations in the human CRT1 have been identified (Table 4), a large fraction of which code for missense variants (Farr, El-Kasaby, Freissmuth, & Sucic, 2020). ...
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Neurotransmitters, such as γ-aminobutyric acid, glutamate, acetyl choline, glycine and the monoamines, facilitate the crosstalk within the central nervous system. The designated neurotransmitter transporters (NTTs) both release and take up neurotransmitters to and from the synaptic cleft. NTT dysfunction can lead to severe pathophysiological consequences, e.g. epilepsy, intellectual disability, or Parkinson's disease. Genetic point mutations in NTTs have recently been associated with the onset of various neurological disorders. Some of these mutations trigger folding defects in the NTT proteins. Correct folding is a prerequisite for the export of NTTs from the endoplasmic reticulum (ER) and the subsequent trafficking to their pertinent site of action, typically at the plasma membrane. Recent studies have uncovered some of the key features in the molecular machinery responsible for transporter protein folding, e.g., the role of heat shock proteins in fine-tuning the ER quality control mechanisms in cells. The therapeutic significance of understanding these events is apparent from the rising number of reports, which directly link different pathological conditions to NTT misfolding. For instance, folding-deficient variants of the human transporters for dopamine or GABA lead to infantile parkinsonism/dystonia and epilepsy, respectively. From a therapeutic point of view, some folding-deficient NTTs are amenable to functional rescue by small molecules, known as chemical and pharmacological chaperones.
... Creatine (Cr) has been well accepted as an effector in muscle, however several lines of evidence suggest a role for Cr in cognition (as reviewed in [1,2]). An endogenous amino acid, Cr is synthesized from glycine, arginine, and S-adenosylmethionine in several organs, including the brain [3]. ...
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The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr (w/w)) diet for 8–9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enhancements with Cr supplementation in both sexes. In females, Cr supplementation increased CREB phosphorylation and levels of IκB (NF-κB suppressor), CaMKII, PSD-95, and high-molecular-weight amyloid β (Aβ) species, whereas Aβ trimers were reduced. These data suggest a beneficial preventative effect of Cr supplementation in females and warrant caution against Cr supplementation in males in the AD-like brain.
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The creatine kinase system is crucial for maintaining cellular energy homeostasis and plays a role in regulating locomotor behavior in organisms, but its significance in the regulating the motionless behavior in olive flounder is limited. In the first experiment of this study, elevated levels of creatine kinase (CK) activity in the spinal cord were detected in the juvenile group (JG) flounder compared to the adult group (AG) flounder. In the second experiment, to further confirm the involvement of CK in the locomotor behavior, the adult flounder was given an intraperitoneal injection of creatine (150 mg/kg), while the flounder in the control group received a saline solution. After one week post-injection, the behavioral analysis revealed that the flounder in the creatine-treated group displayed higher levels of locomotor activity and a greater number of escape attempts in response to external stimuli when compared to the control group. However, the acute stress response, induced by intraperitoneal injection and characterized by tail beating, was significantly alleviated in the flounder in the creatine-treated group. Additionally, there was an upregulation of the UII and AchR genes in the spinal cord, as well as increased levels of UII and AchR in the muscle tissues of the creatine-treated flounder. However, a reduction in UI mRNA levels was observed in the brain of the flounder. Collectively, our data provide the evidence that the elevated enzyme activity and gene expression of creatine kinase play important roles in off-bottom swimming behavior in the JG flounder. Furthermore, administration of creatine improved the locomotor activity and alleviated the stress response in flounder, which is associated with regulation of the locomotor- and stress-related gene in the brain, spinal cord, and muscle.
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Traumatic brain injuries (TBIs) constitute a significant public health issue and a major source of disability and death in the United States and worldwide. TBIs are strongly associated with high morbidity and mortality rates, resulting in a host of negative health outcomes and long-term complications and placing a heavy financial burden on healthcare systems. One promising avenue for the prevention and treatment of brain injuries is the design of TBI-specific supplementation and dietary protocols centred around nutraceuticals and biochemical compounds whose mechanisms of action have been shown to interfere with, and potentially alleviate, some of the neurophysiological processes triggered by TBI. For example, evidence suggests that creatine monohydrate and omega-3 fatty acids (DHA and EPA) help decrease inflammation, reduce neural damage and maintain adequate energy supply to the brain following injury. Similarly, melatonin supplementation may improve some of the sleep disturbances often experienced post-TBI. The scope of this narrative review is to summarise the available literature on the neuroprotective effects of selected nutrients in the context of TBI-related outcomes and provide an evidence-based overview of supplementation and dietary protocols that may be considered in individuals affected by—or at high risk for—concussion and more severe head traumas. Prophylactic and/or therapeutic compounds under investigation include creatine monohydrate, omega-3 fatty acids, BCAAs, riboflavin, choline, magnesium, berry anthocyanins, Boswellia serrata, enzogenol, N-Acetylcysteine and melatonin. Results from this analysis are also placed in the context of assessing and addressing important health-related and physiological parameters in the peri-impact period such as premorbid nutrient and metabolic health status, blood glucose regulation and thermoregulation following injury, caffeine consumption and sleep behaviours. As clinical evidence in this research field is rapidly emerging, a comprehensive approach including appropriate nutritional interventions has the potential to mitigate some of the physical, neurological, and emotional damage inflicted by TBIs, promote timely and effective recovery, and inform policymakers in the development of prevention strategies.
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Introduction: Hippocampal atrophy is an established biomarker for conversion from the normal ageing process to developing cognitive impairment and dementia. This study used a novel hypothesis-free machine-learning approach, to uncover potential risk factors of lower hippocampal volume using information from the world's largest brain imaging study. Methods: A combination of machine learning and conventional statistical methods were used to identify predictors of low hippocampal volume. We run gradient boosting decision tree modelling including 2891 input features measured before magnetic resonance imaging assessments (median 9.2 years, range 4.2-13.8 years) using data from 42,152 dementia-free UK Biobank participants. Logistic regression analyses were run on 87 factors identified as important for prediction based on Shapley values. False discovery rate adjusted P-value <0.05 was used to declare statistical significance. Results: Older age, male sex, greater height, and whole-body fat free mass were the main predictors of low hippocampal volume with the model also identifying associations with lung function and lifestyle factors including smoking, physical activity, and coffee intake (corrected P<0.05 for all). Red blood cell count and several red blood cell indices such as haemoglobin concentration, mean corpuscular haemoglobin, mean corpuscular volume, mean reticulocyte volume, mean sphered cell volume, and red blood cell distribution width were among many biomarkers associated with low hippocampal volume. Conclusion: Lifestyles, physical measures, and biomarkers may affect hippocampal volume, with many of the characteristics potentially reflecting oxygen supply to the brain. Further studies are required to establish causality and clinical relevance of these findings.
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The discovery of a new neurotransmitter, especially one in the central nervous system, is both important and difficult. We have been searching for new neurotransmitters for 12 y. We detected creatine (Cr) in synaptic vesicles (SVs) at a level lower than glutamate and gamma-aminobutyric acid but higher than acetylcholine and 5-hydroxytryptamine. SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in Slc6a8 and Agat mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP-dependent manner. Our biochemical, chemical, genetic, and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter, though not yet reaching the level of proof for the now classic transmitters. Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.
Preprint
Full-text available
The discovery of a new neurotransmitter, especially one in the central nervous system (CNS), is both important and difficult. We have been searching for new neurotransmitters for 12 years. We detected creatine (Cr) in synaptic vesicles (SVs), at a level lower than glutamate (Glu) and gamma-aminobutyric acid (GABA) but higher than acetylcholine (ACh) and 5-hydroxytryptamine (5-HT). SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (AGAT, a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability (ID) in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in SLC6A8 and AGAT mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP dependent manner. Our biochemical, chemical, genetic and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter, though not yet reaching the level of proof for the now classic transmitters. Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.
Preprint
Full-text available
The discovery of a new neurotransmitter, especially one in the central nervous system (CNS), is both important and difficult. We have been searching for new neurotransmitters for 12 years. We detected creatine (Cr) in synaptic vesicles (SVs), at a level lower than glutamate (Glu) and gamma-aminobutyric acid (GABA) but higher than acetylcholine (ACh) and 5-hydroxytryptamine (5-HT). SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (AGAT, a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability (ID) in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in SLC6A8 and AGAT mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP dependent manner. Our biochemical, chemical, genetic and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter.Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.
Preprint
Full-text available
It has never been easy to discover a new neurotransmitter, especially one in the central nervous system (CNS). We have been searching for new neurotransmitters for 12 years. We detected creatine (Cr) in synaptic vesicles (SVs), at a level lower than glutamate (Glu) and gamma-aminobutyric acid (GABA) but higher than acetylcholine (ACh) and 5-hydroxytryptamine (5-HT). SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (AGAT, a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability (ID) in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in SLC6A8 and AGAT mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP dependent manner. Thus, our biochemical, chemical, genetic and electrophysiological results suggest Cr as a neurotransmitter, illustrate a novel approach to discover neurotransmitters and provide a new basis for ID pathogenesis.
Preprint
Full-text available
It has never been easy to discover a new neurotransmitter, especially one in the central nervous system (CNS). We have been searching for new neurotransmitters for 12 years. We detected creatine (Cr) in synaptic vesicles (SVs), at a level lower than glutamate (Glu) and gamma-aminobutyric acid (GABA) but higher than acetylcholine (ACh) and 5-hydroxytryptamine (5-HT). SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (AGAT, a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability (ID) in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in SLC6A8 and AGAT mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP dependent manner. Thus, our biochemical, chemical, genetic and electrophysiological results suggest Cr as a neurotransmitter, illustrate a novel approach to discover neurotransmitters and provide a new basis for ID pathogenesis.
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While skeletal muscle creatine levels can be enhanced by exogenous creatine supplementation, the elevation of brain creatine levels with oral creatine administration remains a challenge due to a lack of effective transportation of creatine through the blood-brain barrier. Intranasal administration can bypass the blood-brain barrier and deliver drugs directly to the brain. The purpose of this study was to assess the effect of intranasal administration of creatine on brain creatine level and cognitive performance. Rats were randomly assigned into three groups intranasal administration group, oral administration group, and control group. The intranasal group exhibited fewer errors and shorter primary latency compared to the control and oral groups, respectively, during the acquisition phase of the Barnes maze. The intranasal group spent a higher percentage of time in the target quadrant during the probe trial compared to the control group. Biochemical measurements showed that the concentration of creatine in the olfactory bulbs, medial prefrontal cortex, and hippocampus of the rats in the intranasal group was higher than in the oral, and control groups. These results indicate that intranasal administration of creatine hydrochloride increases the creatine level in the rat's brain's and improves their performance in the Barnes maze.
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Aims: There is evidence that both aging and increased adiposity may impact creatine levels in the brain, and brain cre-atine levels are important for cognition. The aim of this study was to assess correlation between dietary creatine intake and cognition in in elderly women with overweight. Methods: Twenty seven overweight women over 60 years of age who were part of a larger study participated in an Eriksen Flanker Task (EFT) to asssess cognitive performance. Additionally, diet was assessed over 5 days via daily diary nutritional recalls and the estimate of the daily amount of cre-atine was calculated. Results: In the EFT when incongruente stimulus were presented there was a significant diferences between those with low and high intake of creatine (−35.3 ± 5.84; p < 0.001). Similarly, reaction time to answer incon-gruent stimulus (r = −0.383; p = 0.004) and the percent of correct answers (r = 0.743; p < 0.001) showed weak to strong correlations with self-reported daily creatine intake. Conclusions: In conclusion, our results suggest that in elderly women with overweight that dietary intake of creatine may influence cognitive ability. Clinical Implications: Our findings support the idea that intake of dietary creatine may be an important factor for cognition in older adults.
Chapter
Traumatic brain injury and the susceptibility to secondary injury pose a public health problem with a substantial financial burden on the society. Current researches suggest that consumption of certain diets or their associated physiologically active constituents may be linked to disease risk reduction. This chapter reviews some of the extensively explored dietary supplements like eicosapentaenoic acid, docosahexaenoic acid, creatine, vitamins, zinc, magnesium, and their clinical interventions for the treatment of TBI and recovery from the tissue damage. On the brighter side, there appear to be no adverse effects to any of these dietary supplements, when used appropriately. The major challenges of the future are performing well-designed clinical studies in patients to confirm anticipated effects, to define the optimal doses, to compare single vs multiple dietary components, and to assess possible side effects.
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Aims: The purpose was to examine the relationship between habitual dietary creatine intake obtained in food and visuo-spatial short-term memory (VSSM). Methods: Forty-two participants (32 females, 10 males; > 60 yrs of age) completed a 5-day dietary recall to estimate creatine intake and performed a cognitive assessment which included a visuospatial short-term memory test (forward and reverse corsi block test) and a mini-mental state examination (MMSE). Pearson correlation coefficients were determined. Further, cohorts were derived based on the median creatine intake. Results: There was a significant correlation between the forward Corsi (r = 0.703, P < 0.001), reverse Corsi (r = 0.715, P < 0.001), and the memory sub-component of the MMSE (r = 0.406, P = 0.004). A median creatine intake of 0.382 g/day was found. Participants consuming greater than the median had a significantly higher Corsi (P = 0.005) and reverse Corsi (P < 0.001) scores compared to participants ingesting less than the median. Conclusions: Dietary creatine intake is positively associated with measures of memory in older adults. Clinical Implications: Older adults should consider food sources containing creatine (i.e. red meat, seafood) due to the positive association with visuospatial short-term memory.
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Aims To explore the possible metabolic alterations of bilateral dorsolateral prefrontal cortices (DLPFC) of generalized tonic-clonic seizures (GTCS) patients before and after antiepileptic drugs treatment as compared with healthy controls (HCs) using proton magnetic resonance spectroscopy (1H-MRS). Methods We included 23 newly diagnosed and unmedicated GTCS patients and 23 sex- and age-matched HCs. Metabolites including N-acetyl aspartate (NAA), myo-inositol (Ins), choline (Cho), creatine (Cr), and glutamate + glutamine (Glu + Gln, Glx) concentrations were quantified by using LCModel software and then corrected for the partial volume effect of cerebrospinal fluid. Results The results demonstrated that metabolite concentrations were not equal between the left and the right DLPFC. Compared with HC, NAA of the left DLPFC and Cr of the right DLPFC were significantly lower in pre-treatment patients. Self-controlled study revealed that the patients’ NAA of the left DLPFC increased while their Cr of the right DLPFC decreased after treatment. Correlation analysis showed a negative correlation between the duration of medication and the pre- and post-treatment difference of Cr. Conclusion These findings may shed a light on the metabolic mechanism of GTCS and the neurobiochemical mechanisms of AEDs.
Chapter
Creatine is one of the most popular supplements worldwide, and it is frequently used by both athletic and nonathletic populations to improve power, strength, muscle mass, and performance. However, new uses for creatine are emerging, as it seems to have therapeutic effects in a wide variety of clinical conditions, such as insulin insensitivity, cancer, muscle, bone, and cartilage disorders. Creatine have also been reported to influence the brain and to have therapeutic applications to many neurological disorders such as creatine supplementation has been shown to improve mental fatigue, memory, and attention, to reduce oxidative stress, and to control the progression of some neurodegenerative diseases. The combination of these benefits has made creatine as a strong candidate for therapeutic use against age-related diseases, such as long-term memory impairments, amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease. In this chapter, we explore the therapeutic potential of creatine supplementation to improve diseases and disorders associated with aging brain.
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Gender-related rates of depression and suicidality implicate a double gender paradox: while the life-time risk of depression in women is two to three times higher compared to men, their suicide rate is low, but their rate of attempted suicides is three times higher compared to men. In contrast, the suicide rate in men is at least three times higher, but their depression rate amounts to only half the women's rate. Although this has been well-known for a long time existing explanations are not sufficient. In this paper, depression and suicidality are explained in the context of gender-related stress exposure, stress vulnerability and stress response. In particular, the question is discussed whether the concept of male depression contributes to explain the gender paradox in depression and suicide in men.
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To date, functional 1H NMR spectroscopy has been utilized to report the time courses of few metabolites, primarily lactate. Benefiting from the sensitivity offered by ultra-high magnetic field (7 T), the concentrations of 17 metabolites were measured in the human visual cortex during two paradigms of visual stimulation lasting 5.3 and 10.6 mins. Significant concentration changes of approximately 0.2 μmol/g were observed for several metabolites: lactate increased by 23%±5% (P
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There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. clinicaltrials.gov Identifier: NCT00449865.
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Creatine is a naturally occurring compound involved in the buffering, transport and regulation of cellular energy. Dietary creatine supplementation has been associated with improved symptoms in neurological disorders defined by impaired neural energy provision. Creatine is also neuroprotective in vitro against anoxic/hypoxic damage. The utility of creatine to protect against energetic insult in vivo remains to be investigated in humans. The aim of this study was to assess the influence of oral creatine supplementation on neurophysiological and neuropsychological function during acute oxygen deprivation. 14 healthy volunteers (8 males) participated in a week-long placebo-controlled creatine monohydrate supplementation protocol within a double-blind, crossover design. Creatine concentration in the sensorimotor cortex was 10% greater following supplementation (Cr: 7.0 ± 1.6 mmol/L, Pla: 6.4 ± 0.9 mmol/L; p = 0.04) as measured using magnetic resonance spectroscopy. A 90 min hypoxic gas (FiO2 = 0.10) breathing protocol severely reduced arterial oxygen saturation (p < 0.01) in both treatments (SaO2, Cr: 79 ± 8%, Pla: 79 ± 11%) and impaired a wide range of neuropsychological processes. A composite neurocognitive index score was reduced by 12 ± 20% (p = 0.02). Impairments were most pronounced for measures of attention (complex attention: -29 ± 55%; p = 0.03). Corticomotor excitability increased in response to hypoxia with creatine supplementation (Δ ΣMEP, Cr: 170 ± 91% vs. Pla: 127 ± 60%; p = 0.04) and restored hypoxia-induced decrements in neuropsychological performance (neurocognitive index -4 ± 12%, complex attention: -8 ± 18%). Dietary creatine monohydrate supplementation augments neural creatine, increases corticomotor excitability, and prevents decline in cognition that occurs during severe oxygen deficit. Creatine monohydrate has potential utility as a neuroprotective supplement when cellular energy provision is compromised.
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Impairment or interruption of oxygen supply compromises brain function and plays a role in neurological and neurodegenerative conditions. Creatine is a naturally occurring compound involved in the buffering, transport, and regulation of cellular energy, with the potential to replenish cellular adenosine triphosphate without oxygen. Creatine is also neuroprotective in vitro against anoxic/hypoxic damage. Dietary creatine supplementation has been associated with improved symptoms in neurological disorders defined by impaired neural energy provision. Here we investigate, for the first time in humans, the utility of creatine as a dietary supplement to protect against energetic insult. The aim of this study was to assess the influence of oral creatine supplementation on the neurophysiological and neuropsychological function of healthy young adults during acute oxygen deprivation. Fifteen healthy adults were supplemented with creatine and placebo treatments for 7 d, which increased brain creatine on average by 9.2%. A hypoxic gas mixture (10% oxygen) was administered for 90 min, causing global oxygen deficit and impairing a range of neuropsychological processes. Hypoxia-induced decre-ments in cognitive performance, specifically attentional capacity, were restored when participants were creatine supplemented, and corticomotor excitability increased. A neuromodulatory effect of creatine via increased energy availability is presumed to be a contrib-uting factor of the restoration, perhaps by supporting the maintenance of appropriate neuronal membrane potentials. Dietary creatine monohydrate supplementation augments neural creatine, increases corticomotor excitability, and prevents the decline in attention that occurs during severe oxygen deficit. This is the first demonstration of creatine's utility as a neuroprotective supplement when cellular energy provision is compromised.
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The inhibitory neurotransmitter γ-aminobutyric acid (GABA) acts through various types of receptors in the central nervous system. GABAρ receptors, defined by their characteristic pharmacology and presence of ρ subunits in the channel structure, are poorly understood and their role in the cortex is ill-defined. Here, we used a targeted pharmacological, NMR-based functional metabolomic approach in Guinea pig brain cortical tissue slices to identify a distinct role for these receptors. We compared metabolic fingerprints generated by a range of ligands active at GABAρ and included these in a principal components analysis with a library of other metabolic fingerprints obtained using ligands active at GABAA and GABAB, with inhibitors of GABA uptake and with compounds acting to inhibit enzymes active in the GABAergic system. This enabled us to generate a metabolic “footprint” of the GABAergic system which revealed classes of metabolic activity associated with GABAρ which are distinct from other GABA receptors. Antagonised GABAρ produce large metabolic effects at extrasynaptic sites suggesting they may be involved in tonic inhibition.
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The modulation of N-methyl-D-aspartate receptor (NMDAR) and l-arginine/nitric oxide (NO) pathway is a therapeutic strategy for treating depression and neurologic disorders that involves excitotoxicity. Literature data have reported that creatine exhibits antidepressant and neuroprotective effects, but the implication of NMDAR and l-arginine/nitric oxide (NO) pathway in these effects is not established. This study evaluated the influence of pharmacological agents that modulate NMDAR/l-arginine-NO pathway in the anti-immobility effect of creatine in the tail suspension test (TST) in mice. The NOx levels and cellular viability in hippocampal and cerebrocortical slices of creatine-treated mice were also evaluated. The anti-immobility effect of creatine (10 mg/kg, po) in the TST was abolished by NMDA (0.1 pmol/mouse, icv), d-serine (30 µg/mouse, icv, glycine-site NMDAR agonist), arcaine (1 mg/kg, ip, polyamine site NMDAR antagonist), l-arginine (750 mg/kg, ip, NO precursor), SNAP (25 μg/mouse, icv, NO donor), L-NAME (175 mg/kg, ip, non-selective NOS inhibitor) or 7-nitroindazole (50 mg/kg, ip, neuronal NOS inhibitor), but not by DNQX (2.5 µg/mouse, icv, AMPA receptor antagonist). The combined administration of sub-effective doses of creatine (0.01 mg/kg, po) and NMDAR antagonists MK-801 (0.001 mg/kg, po) or ketamine (0.1 mg/kg, ip) reduced immobility time in the TST. Creatine (10 mg/kg, po) increased cellular viability in hippocampal and cerebrocortical slices and enhanced hippocampal and cerebrocortical NOx levels, an effect potentiated by l-arginine or SNAP and abolished by 7-nitroindazole or L-NAME. In conclusion, the anti-immobility effect of creatine in the TST involves NMDAR inhibition and enhancement of NO levels accompanied by an increase in neural viability.
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The present cross-sectional study aimed to examine the influence of diet on brain creatine (Cr) content by comparing vegetarians with omnivores. Brain Cr content in the posterior cingulate cortex was assessed by proton magnetic resonance spectroscopy (1H-MRS). Dietary Cr intake was assessed by 3 d food recalls. Vegetarians had lower dietary Cr intake than omnivores (0·03 (sd 0·01) v. 1·34 (sd 0·62) g/d, respectively; P= 0·005). However, vegetarians and omnivores had comparable brain total Cr content (5·999 (sd 0·811) v. 5·917 (sd 0·665) IU, respectively; P= 0·77). In conclusion, dietary Cr did not influence brain Cr content in healthy individuals, suggesting that in normal conditions brain is dependent on its own Cr synthesis.
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Identification of risk factors and prodromal markers for Parkinson's disease (PD) and the understanding of the point in time of first occurrence is essential for the early detection of incident PD. In this three-center longitudinal, observational study, we evaluated the specific risk for PD associated with single or combinations of risk factors and prodromal markers. In addition, we evaluated which risk factors and prodromal markers emerge at which time before the diagnosis of PD. Of the 1,847 at-baseline PD-free individuals ≥50 years, 1,260 underwent the 5-year follow-up assessment. There were 21 cases of incident PD during the study period. Enlarged hyperechogenic substantia nigra was the most frequent baseline sign in individuals developing PD after 3 years (80.0 %) and 5 years (85.7 %) compared to healthy controls (17.5 %) followed by the occurrence of mild parkinsonian signs and hyposmia. Evaluation of the signs at the first follow-up assessment showed that individuals developing PD after two additional years showed the same pattern of signs as individuals who developed PD 3 years after baseline assessment.
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To assess the effects of creatine supplementation, associated or not with strength training, upon emotional and cognitive measures in older woman. This is a 24-week, parallel-group, double-blind, randomized, placebo-controlled trial. The individuals were randomly allocated into one of the following groups (n=14 each): 1) placebo, 2) creatine supplementation, 3) placebo associated with strength training or 4) creatine supplementation associated with strength training. According to their allocation, the participants were given creatine (4 x 5 g/d for 5 days followed by 5 g/d) or placebo (dextrose at the same dosage) and were strength trained or not. Cognitive function, assessed by a comprehensive battery of tests involving memory, selective attention, and inhibitory control, and emotional measures, assessed by the Geriatric Depression Scale, were evaluated at baseline, after 12 and 24 weeks of the intervention. Muscle strength and food intake were evaluated at baseline and after 24 weeks. After the 24-week intervention, both training groups (ingesting creatine supplementation and placebo) had significant reductions on the Geriatric Depression Scale scores when compared with the non-trained placebo group (p = 0.001 and p = 0.01, respectively) and the non-trained creatine group (p < 0.001 for both comparison). However, no significant differences were observed between the non-trained placebo and creatine (p = 0.60) groups, or between the trained placebo and creatine groups (p = 0.83). Both trained groups, irrespective of creatine supplementation, had better muscle strength performance than the non-trained groups. Neither strength training nor creatine supplementation altered any parameter of cognitive performance. Food intake remained unchanged. Creatine supplementation did not promote any significant change in cognitive function and emotional parameters in apparently healthy older individuals. In addition, strength training per se improved emotional state and muscle strength, but not cognition, with no additive effects of creatine supplementation. Clinicaltrials.gov NCT01164020.
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Creatine transport has been assigned to creatine transporter 1 (CRT1), encoded by mental retardation associated SLC6A8. Here, we identified a second creatine transporter (CRT2) known as monocarboxylate transporter 12 (MCT12), encoded by the cataract and glucosuria associated gene SLC16A12. A non-synonymous alteration in MCT12 (p.G407S) found in a patient with age-related cataract (ARC) leads to a significant reduction of creatine transport. Furthermore, Slc16a12 knockout (KO) rats have elevated creatine levels in urine. Transport activity and expression characteristics of the two creatine transporters are distinct. CRT2 (MCT12)-mediated uptake of creatine was not sensitive to sodium and chloride ions or creatine biosynthesis precursors, breakdown product creatinine or creatine phosphate. Increasing pH correlated with increased creatine uptake. Michaelis–Menten kinetics yielded a Vmax of 838.8 pmol/h/oocyte and a Km of 567.4 µm. Relative expression in various human tissues supports the distinct mutation-associated phenotypes of the two transporters. SLC6A8 was predominantly found in brain, heart and muscle, while SLC16A12 was more abundant in kidney and retina. In the lens, the two transcripts were found at comparable levels. We discuss the distinct, but possibly synergistic functions of the two creatine transporters. Our findings infer potential preventive power of creatine supplementation against the most prominent age-related vision impaired condition.
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Transcranial direct current stimulation is an emerging treatment for brain disorders but its mode of action is not well understood. We applied 10 min 1 mA anodal transcranial direct current stimulation (tDCS) inside the bore of a 3 T MRI scanner to the left dorsolateral prefrontal cortex of 13 healthy volunteers (aged 19-28 yr) in a blinded, sham-controlled, cross-over design. Brain bioenergetics were measured from the left temporo-frontal region using 31P magnetic resonance spectroscopy before, during and for 20 min following tDCS. Brain pH rose during tDCS and remained elevated afterwards. Phosphomonoesters were significantly decreased while inorganic phosphate (Pi) also fell. Partial-least squares discriminant analysis of the data revealed two significantly different subject groups: one where phosphocreatine (PCr), ATP and Pi fell along with a larger increase in pH and one where PCr and ATP increased along with a smaller increase in pH and a slower and more sustained decrease in Pi. Group membership was predicted by baseline pH and ATP. We interpreted the effects of tDCS as driving two biochemical processes: cellular consumption of ATP causing hydrolysis of PCr via the creatine kinase reaction driving the increase in pH; synthesis of ATP and PCr by mitochondria with concomitant drop in Pi and phosphomonoester levels.
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Objective: Antidepressants targeting monoaminergic neurotransmitter systems, despite their immediate effects at the synaptic level, usually require several weeks of administration to achieve clinical efficacy. The authors propose a strategy of adding creatine monohydrate (creatine) to a selective serotonin reuptake inhibitor (SSRI) in the treatment of patients with major depressive disorder. Such augmentation may lead to a more rapid onset of antidepressant effects and a greater treatment response, potentially by restoring brain bioenergetics at the cellular level. Method: Fifty-two women with major depressive disorder were enrolled in an 8-week double-blind placebo-controlled clinical trial and randomly assigned to receive escitalopram in addition to either creatine (5 g/day, N=25) or placebo (N=27). Efficacy was primarily assessed by changes in the Hamilton Depression Rating Scale (HAM-D) score. Results: In comparison to the placebo augmentation group, patients receiving creatine augmentation showed significantly greater improvements in HAM-D score, as early as week 2 of treatment. This differential improvement favoring creatine was maintained at weeks 4 and 8. There were no differences between treatment groups in the proportion of patients who discontinued treatment prematurely (creatine: N=8, 32.0%; placebo: N=5, 18.5%) or in the overall frequency of all reported adverse events (creatine: 36 events; placebo: 45 events). Conclusions: The current study suggests that creatine augmentation of SSRI treatment may be a promising therapeutic approach that exhibits more rapid and efficacious responses in women with major depressive disorder.
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Creatine deficiency syndromes (CDS) are a group of inborn errors of creatine synthesis and transport and include autosomal recessive arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) deficiencies, and deficiency of the X-linked creatine transporter (SLC6A8). In all these disorders the common clinical hallmark is mental retardation, speech delay and epilepsy. Additional frequent manifestations include failure to thrive, growth retardation, muscular hypotonia and movement disorder (mainly extrapyramidal). The common biochemical hallmark is cerebral creatine deficiency as detected by proton magnetic resonancespectroscopy (H-MRS).
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Guanidinoacetic acid (GAA) is the biosynthetic precursor of creatine which is involved in storage and transmission of phosphate-bound energy. Hepatocytes readily convert GAA to creatine, raising the possibility that the active uptake of GAA by hepatocytes is a regulatory factor. The purpose of this study is to investigate and identify the transporter responsible for GAA uptake by hepatocytes. The characteristics of [(14)C]GAA uptake by hepatocytes were elucidated using the in vivo liver uptake method, freshly isolated rat hepatocytes, an expression system of Xenopus laevis oocytes, gene knockdown, and an immunohistochemical technique. In vivo injection of [(14)C]GAA into the rat femoral vein and portal vein results in the rapid uptake of [(14)C]GAA by the liver. The uptake was markedly inhibited by γ-aminobutyric acid (GABA) and nipecotinic acid, an inhibitor of GABA transporters (GATs). The characteristics of Na(+)- and Cl(-)-dependent [(14)C]GAA uptake by freshly isolated rat hepatocytes were consistent with those of GAT2. The Km value of the GAA uptake (134 µM) was close to that of GAT2-mediated GAA transport (78.9 µM). GABA caused a marked inhibition with an IC(50) value of 8.81 µM. The [(14)C]GAA uptake exhibited a significant reduction corresponding to the reduction in GAT2 protein expression. GAT2 was localized on the sinusoidal membrane of the hepatocytes predominantly in the periportal region. This distribution pattern was consistent with that of the creatine biosynthetic enzyme, S-adenosylmethionine:guanidinoacetate N-methyltransferase. GAT2 makes a major contribution to the sinusoidal GAA uptake by periportal hepatocytes, thus regulating creatine biosynthesis in the liver.
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J. Neurochem. (2011) 10.1111/j.1471-4159.2011.07525.x Mitochondria are key contributors to many forms of cell death including those resulting from neonatal hypoxic-ischemic brain injury. Mice have become increasingly popular in studies of brain injury, but there are few reports evaluating mitochondrial isolation procedures for the neonatal mouse brain. Using evaluation of respiratory activity, marker enzymes, western blotting and electron microscopy, we have compared a previously published procedure for isolating mitochondria from neonatal mouse brain (method A) with procedures adapted from those for adult rats (method B) and neonatal rats (method C). All three procedures use Percoll density gradient centrifugation as a key step in the isolation but differ in many aspects of the fractionation procedure and the solutions used during fractionation. Methods A and B both produced highly enriched fractions of well-coupled mitochondria with high rates of respiratory activity. The fraction from method C exhibited less preservation of respiratory properties and was more contaminated with other subcellular components. Method A offers the advantage of being more rapid and producing larger mitochondrial yields making it useful for routine applications. However, method B produced mitochondria that were less contaminated with synaptosomes and associated cytosolic components that suits studies that have a requirement for higher mitochondrial purification.
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The blood-oxygenation level dependent (BOLD) haemodynamic response function (HDR) in functional magnetic resonance imaging (fMRI) is a delayed and indirect marker of brain activity. In this single case study a small BOLD response synchronised with the stimulus paradigm is found globally, i.e. in all areas outside those of expected activation in a single subject study. The nature of the global response has similar shape properties to the archetypal BOLD HDR, with an early positive signal and a late negative response typical of the negative overshoot. Fitting Poisson curves to these responses showed that voxels were potentially split into two sets: one with dominantly positive signal and the other predominantly negative. A description, quantification and mapping of the global BOLD response is provided along with a 2 × 2 classification table test to demonstrate existence with very high statistical confidence. Potential explanations of the global response are proposed in terms of 1) global HDR balancing; 2) resting state network modulation; and 3) biological systems synchronised with the stimulus cycle. Whilst these widespread and low-level patterns seem unlikely to provide additional information for determining activation in functional neuroimaging studies as conceived in the last 15 years, knowledge of their properties may assist more comprehensive accounts of brain connectivity in the future.
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The role of ubiquitous mitochondrial creatine kinase (uMtCK) reaction in regulation of mitochondrial respiration was studied in purified preparations of rat brain synaptosomes and mitochondria. In permeabilized synaptosomes, apparent Km for exogenous ADP, Km (ADP), in regulation of respiration in situ was rather high (110 ± 11 μM) in comparison with isolated brain mitochondria (9 ± 1 μM). This apparent Km for ADP observed in isolated mitochondria in vitro dramatically increased to 169 ± 52 μM after their incubation with 1 μM of dimeric tubulin showing that in rat brain, particularly in synaptosomes, mitochondrial outer membrane permeability for ADP, and ATP may be restricted by tubulin binding to voltage dependent anion channel (VDAC). On the other hand, in synaptosomes apparent Km (ADP) decreased to 25 ± 1 μM in the presence of 20 mM creatine. To fully understand this effect of creatine on kinetics of respiration regulation, complete kinetic analysis of uMtCK reaction in isolated brain mitochondria was carried out. This showed that oxidative phosphorylation specifically altered only the dissociation constants for MgATP, by decreasing that from ternary complex MtCK.Cr.MgATP (K a) from 0.13 ± 0.02 to 0.018 ± 0.007 mM and that from binary complex MtCK.MgATP (K ia) from 1.1 ± 0.29 mM to 0.17 ± 0.07 mM. Apparent decrease of dissociation constants for MgATP reflects effective cycling of ATP and ADP between uMtCK and adenine nucleotide translocase (ANT). These results emphasize important role and various pathophysiological implications of the phosphocreatine–creatine kinase system in energy transfer in brain cells, including synaptosomes.
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The creatine transporter (CRTR) defect is a recently discovered cause of X-linked intellectual disability for which treatment options have been explored. Creatine monotherapy has not proved effective, and the effect of treatment with L-arginine is still controversial. Nine boys between 8 months and 10 years old with molecularly confirmed CRTR defect were followed with repeated (1)H-MRS and neuropsychological assessments during 4-6 years of combination treatment with creatine monohydrate, L-arginine, and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with H(1)-MRS. After an initial improvement in locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionally, we noticed an age-related decline in IQ subscales in boys affected with the CRTR defect.
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Creatine when combined with P forms phosphocreatine that acts as a reserve of high-energy phosphate. Creatine is found mostly in meat, fish and other animal products, and the levels of muscle creatine are known to be lower in vegetarians. Creatine supplementation influences brain functioning as indicated by imaging studies and the measurement of oxygenated Hb. Given the key role played by creatine in the provision of energy, the influence of its supplementation on cognitive functioning was examined, contrasting the effect in omnivores and vegetarians. Young adult females (n 128) were separated into those who were and were not vegetarian. Randomly and under a double-blind procedure, subjects consumed either a placebo or 20 g of creatine supplement for 5 d. Creatine supplementation did not influence measures of verbal fluency and vigilance. However, in vegetarians rather than in those who consume meat, creatine supplementation resulted in better memory. Irrespective of dietary style, the supplementation of creatine decreased the variability in the responses to a choice reaction-time task.
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Creatine monohydrate is an organic acid that plays a key role in ATP re-synthesis. Creatine levels in the human brain vary considerably and dietary supplementation has been found to enhance cognitive performance in healthy individuals. To explore the possibility that the fMRI Blood Oxygen Level Dependent (BOLD) response is influenced by creatine levels, BOLD responses to visual stimuli were measured in visual cortex before and after a week of creatine administration in healthy human volunteers. The magnitude of the BOLD response decreased by 16% following creatine supplementation of a similar dose to that previously shown to increase cerebral levels of phosphocreatine. We also confirmed that cognitive performance (memory span) is increased. These changes were not found in a placebo group. Possible mechanisms of BOLD change are considered. The results offer potential for insight into the coupling between neural activity and the BOLD response and the more immediate possibility of accounting for an important source of variability during fMRI analysis in clinical studies and other investigations where between-subjects variance is an issue.
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Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus ((31)P) MRS. (31)P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21-84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (-0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p = 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using (31)P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non-demented and psychiatrically stable older adults and specifically analyzed gray-white matter differences in brain metabolism.
Article
The supplementation of creatine (Cr) has a marked neuroprotective effect in mouse models of neurodegenerative diseases. This has been assigned to the known bioenergetic, anti-apoptotic, anti-excitotoxic and anti-oxidant properties of Cr. As aging and neurodegeneration share pathophysiological pathways, we investigated the effect of oral Cr supplementation on aging in 162 aged C57Bl/6J mice. Outcome variables included healthy life span, neurobehavioral phenotyping, as well as morphology, biochemistry and expression profiling from brain. The median healthy life span of Cr-fed mice was 9% higher than in control mice, and they performed significantly better in neurobehavioral tests. In brains of Cr-treated mice, there was a trend towards a reduction of reactive oxygen species and significantly lower accumulation of the aging pigment lipofuscin. Expression profiling showed an upregulation of genes implicated in neuronal growth, neuroprotection, and learning. These data show that Cr improves health and longevity in mice. Cr may be a promising food supplement to promote healthy human aging.
Chapter
Creatine is synthesized by two enzymatic reactions (◘ Fig. 15.1): 1) L-arginine:glycine amidinotransferase (AGAT, GATM) catalyses the transfer of an amidino group from arginine to glycine, yielding guanidinoacetate; 2) S-adenosyl-L-methionine: N-guanidinoacetatemethyltransferase (GAMT, GAMT) catalyses the methylation of the amidino group in the guanidinoacetate molecule, yielding creatine.
Article
Creatine deficiency syndromes (CDS) are a novel group of inborn errors of creatine synthesis and transport including autosomal recessive arginine:glycine amidino transferase (AGAT) and guanidinoacetate methyltransferase (GAMT) deficiencies, and the X-linked creatine transporter (SLC6A8) deficiency. In all these disorders the common clinical hallmark is mental retardation, expressive speech delay and epilepsy; the common biochemical hallmark is cerebral creatine deficiency as detected by proton magnetic resonance spectroscopy (H-MRS). Increased levels of guanidinoacetic acid (GAA) in body fluids are pathognomonic for GAMT deficiency whereas these levels are reduced in AGAT deficiency. An increased urinary creatine/creatinine ratio is associated with SLC6A8 deficiency. Oral supplementation of creatine leads to partial restoration of the cerebral creatine pool and improvement of clinical symptoms in GAMT and AGAT deficiency. Reduction of GAA by additional dietary restriction of arginine (and supplemen tation of ornithine) appears to be of additional benefit for the long-term outcome of GAMT deficient patients. For SLC6A8 deficient patients no effective treatment is currently available. CDS may account for a considerable fraction of children and adults with mental retardation of unknown cause and, therefore, screening for these disorders (by urinary/plasma metabolites, brain H-MRS and/or DNA approach) should be included in the investigation of this population. Secondary creatine deficiency can be found in OAT deficiency (▶ Chap. 22).