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The effect of pyridoxine administration on melatonin secretion in normal men



To determine pineal response to pyridoxine in normal men. Twelve healthy men were given orally pyridoxine (100 mg) or placebo at 1700h. Serum melatonin levels were determined every 30 minutes with simultaneous measurement of core body temperature between 1700h to 0300h. Polysomnographic sleep recordings were performed between 1800h to 2000h. Serum melatonin levels after both placebo and pyridoxine showed a nocturnal rise occurring at 22:10+/-1:22h and 22:24+/-1:09h, respectively. The melatonin onset, peak, mean and area under the curve (AUC) values after pyridoxine (3.2+/-1.6 pg/ml, 47.2+/-22.6 pg/ml, 31.5+/-11.0 pg/ml and 173.5+/-138.4 pg/ml x min, respectively) were similar to the values after placebo administration (4.7+/-1.6 pg/ml, 53.9+/-26.0 pg/ml, 37.2+/-2.8 pg/ml and 205.3+/-137.8 pg/ml x min, respectively). CBT revealed a significant nocturnal decline but without significant difference between pyridoxine and placebo. Sleep amount and architecture were similar after the two treatments. In adult man, the oral administration of 100 mg-pyridoxine during the evening hours has no effect on melatonin secretion nor does it alter CBT or sleep quality.
Neuroendocrinology Letters ISSN 0172780X
Copyright © 2002 Neuroendocrinology Letters
The effect of pyridoxine administration on melatonin
secretion in normal men
Rafael Luboshitzky
, U. Ophir
, Rachel Nave
, Rachel Epstein
Zila Shen-Orr
& Paula Herer
1. Endocrine Institute, Haemek Medical Center, Afula, Israel.
2. Endocrine Laboratory, Rambam Medical center, Haifa, Israel.
3. Sleep research Laboratory, Technion, Israel Institute of Technology, Haifa, Israel.
Correspondence to: Professor R. Luboshitzky, M.D.
Endocrine Institute,
Haemek Medical Center,
Afula, 18101,
: +972 46495553;
E-MAIL: luboshitzky_ r@
Submitted: April 28, 2002
Accepted: May 1, 2002
Key words: melatonin; core body temperature; sleep; pyridoxine
Neuroendocrinology Letters 2002; 23:213217 pii: NEL230302A02 Copyright © Neuroendocrinology Letters 2002
: To determine pineal response to pyridoxine in normal men.
MATERIAL AND METHODS: Twelve healthy men were given orally pyridoxine
(100 mg) or placebo at 1700h. Serum melatonin levels were determined
every 30 minutes with simultaneous measurement of core body temperature
between 1700h to 0300h. Polysomnographic sleep recordings were performed
between 1800h to 2000h.
RESULTS: Serum melatonin levels after both placebo and pyridoxine showed
a nocturnal rise occurring at 22:10±1:22h and 22:24±1:09h, respectively.
The melatonin onset, peak, mean and area under the curve (AUC) values
after pyridoxine (3.2±1.6 pg/ml, 47.2±22.6 pg/ml, 31.5±11.0 pg/ml and
173.5±138.4 pg/ml x min, respectively) were similar to the values after pla-
cebo administration (4.7±1.6 pg/ml, 53.9±26.0 pg/ml, 37.2±2.8 pg/ml and
205.3±137.8 pg/ml x min, respectively). CBT revealed a signi cant nocturnal
decline but without signi cant difference between pyridoxine and placebo.
Sleep amount and architecture were similar after the two treatments.
CONCLUSIONS: In adult man, the oral administration of 100 mg-pyridoxine
during the evening hours has no effect on melatonin secretion nor does it alter
CBT or sleep quality.
Melatonin, the main hormone produced by the pi-
neal gland, displays a circadian rhythm peaking at
night [1]. Pinealocytes uses tryptophan as substrate
for melatonin synthesis, and melatonin levels change
as a function of tryptophan availability [2]. Pyridox-
ine is converted to its active coenzyme form, pyridoxal
phosphate (PLP). More than 60 PLP-dependent en-
zymes are known, including enzymes that participate
in decarboxylation reactions such as the decarboxyl-
ation of DOPA to dopamine and 5-hydroxytryptophan
to serotonin [34]. The activity of pyridoxine as a co-
enzyme in the tryptophan metabolism was described
in the kinurenine and methoxyindole pathways [5].
Pyridoxine acts as a coenzyme of 5-hydroxytryptophan
decarboxylase. The enzyme carboxylates 5-hydroxy-
tryptophan to serotonin, the immediate precursor of
melatonin [5]. The effect of pyridoxine on aromatic
amino acid decarboxylase activity supports a regula-
tory role of pyridoxine on the synthesis of neurotrans-
mitters [67]. Melatonin was shown to increase brain
pyridoxal phosphokinase activity, inhibition of gluta-
minergic neurotransmission, resulting in inhibitory
effects on central nervous system activity [8]. The
participation of endogenous melatonin in the normal
sleep-wake cycle regulation has been inferred from the
temporal relationships between melatonin cycle and
the 24-hour cycle in sleep propensity, and particularly
between the nocturnal melatonin onset and the noc-
turnal sleep gate [911]. The typical 24-hour sleep pro-
pensity pattern reveals a midafternoon sleepiness peak
followed by a forbidden zone for sleep, which is char-
acterized by very low sleep propensity in the early eve-
ning hours and then followed by the nocturnal sleep
gate. This term refers to a steep rise in sleepiness oc-
curring in the late evening hours [12]. Exogenous mel-
atonin given prior to an early evening nap, during the
forbidden zone for sleep at 18002000h,signi cantly
shortened sleep latency and increased total sleep time.
These data suggested that timed administered melato-
nin can modify sleep propensity [13].
Exogenous melatonin administration has been
shown to lower core body temperature (CBT) by
0.20.4°C [1417]. Acute exposure to bright light at
night elevated the nocturnal CBT and inhibits melato-
nin secretion [18]. This change in CBT was reversed by
a constant infusion of melatonin [19]. The time taken
to reach the maximum drop in CBT following melato-
nin administration was about 3 hours [17].
We hypothesized that pyridoxine may participate
in the nocturnal melatonin secretion and therefor can
modify other circadian rhythms as sleep and tempera-
ture when administered in the late afternoon hours. To
examine this hypothesis, we determined serum mela-
tonin levels, CBT and sleep quality in healthy young
adult men given a single oral dose of pyridoxine or pla-
cebo in the evening hours.
Material and Methods
Subjects and protocol
The study was approved by the institutional review
board (Helsinki committee) and all participants gave
their informed consent before the start of the study.
Twelve healthy males (aged: 2226 years) participated
in the study. Participants were receiving no medica-
tions and during the study they were instructed to re-
frain from smoking, coffee and alcohol, and to have
78 hours of sleep per night, one week prior to the
study. The study comprised of two sessions, two weeks
On each experimental night, an IV catheter was in-
serted in an antecubital vein, kept patent by a slow
infusion of 0.9% NACL. Blood samples (2ml) were
collected every 30 minutes from 1700h to 0300h for
the determination of serum melatonin levels. Rectal
thermistor was inserted to record core body temper-
ature (CBT) between 1700h to 0300h. Subjects were
awake between 17001800h and between 20000300h,
with lights on (50 Lux at eye level) and assumed the
upright posture. Between 1800-2000h subjects were
lying in bed attempting to fall asleep. Conventional
sleep recordings were obtained to verify sleep quality.
Melatonin measurements
Blood was centrifuged, immediately separated and
stored at 20°C until assayed. Serum melatonin levels
were determined by radioimmunoassay (Buhlman
Lab., Albschvill, Switzerland). The assay sensitivity
was 0.3 pg/ml. The intra-assay coef cients of variation
(CV) were 4.9% and 5.8% for low (0.92.6 pg/ml), and
high (9.023.0 pg/ml), respectively. The interassay CVs
were 7.8% and 6.7%, respectively.
Core body temperature
CBT was monitored by rectal thermometer at one-
minute intervals between 17000300h, using the Min-
imitter series 2000 YSI, Yellow-Spring, USA.
Analysis of sleep stages
Electrodes were attached for the following electro-
physiological recordings: two electroencephalograms
(EEG levels C3-A2, C4-A1), two electrooculograms and
one electromyogram of the mentalis. Sleep stages were
scored in 30 seconds epochs according to conventional
criteria [20]. The following parameters were deter-
mined: total recording time (TRT), sleep latency (time
from lights off until 3 consecutive minutes of stage 2),
actual sleep time (AST=TRT sleep latency+waking
periods), rapid eye movement (REM) latency (time
from beginning of sleep to the rst REM episode), sleep
ef ciency (AST/TRT) and percentages of sleep stage
2,3/4, and REM.
Subjects were given an oral dose of 100 mg- pyridox-
ine (vitamin B6, Pyridoxine HCL, Tarima, Maabarot,
Israel) or a look-alike placebo (starch) at 1700h, in a
double blind Latin square design.
Rafael Luboshitzky, U. Ophir, Rachel Nave, Rachel Epstein, Zila Shen-Orr & Paula Herer
Neuroendocrinology Letters ISSN 0172780X Copyright © 2002 Neuroendocrinology Letters
Pyridoxine and melatonin secretion
Statistical analysis
The onset of the nocturnal melatonin rise was de-
ned as the time at which the rst of three consecutive
samples exceeded the mean levels of the day-time val-
ues (17002000h) by more than 1 SD. The integrated
melatonin values were determined as the area under
the curve (AUC) from the time of melatonin onset to
0300h. Independent t test were used to test the differ-
ences in serum melatonin levels, CBT and polysom-
nographic data between pyridoxine and placebo treat-
ments. Data are expressed as mean ± SD.
In this study, we determined serum melatonin lev-
els, core body temperature and sleep quality in 12 men,
aged 23.4±2.6 years, after a single oral dose of 100 mg
pyridoxine or placebo given at 17:00h. Serum melato-
nin onset levels after pyridoxine (3.2 ±1.6 pg/ml) were
lower than the values after placebo (4.7±1.6 pg/ml),
occurring at 22:24±1:09h and 22:10±1:22h, respec-
tively (Table 1). Likewise, peak levels after pyridoxine
(47.2±22.6 pg/ml) were lower than the values after
placebo (53.9±26.0 pg/ml). The integrated amount of
melatonin secreted (area under the curve between
17000300h) after pyridoxine (173.5±138.4 pg/ml x h)
was lower than the value after placebo (205.3±137.8
pg/ml x h). The melatonin values after pyridoxine were
statistically not signi cantly different from the values
after placebo. Core body temperature (CBT) curves
after both treatments were statistically not signi -
cantly different. The peak CBT values after pyri doxine
and placebo were 37°C±0.27 and 36.9±0.26, respec-
tively; occurring at 02:30h ±0:45 and 02:30h ±0:50,
respectively (Figure 1). Quality of sleep was assessed
by actual sleep time and by sleep ef ciency. Sleep ef -
ciency was similar after both treatments and was rela-
tively low (6669%). This is explained by the fact that
subjects had disturbed sleep, probably due to frequent
blood sampling not performed from a separate room
(Table 2).
Table 1. Nocturnal serum melatonin levels after an oral dose of
pyridoxine (100 mg) or placebo given at 1700h in normal men
(Data are mean ± SD)
Melatonin data Pyridoxine Placebo P value
Onset time (clock h) 22:24 ± 1:09 22:10 ± 1:22 NS
Onset level (pg/ml) 3.2 ± 1.6 4.7 ± 1.6 0.09
Peak level (pg/ml) 47.2 ± 22.6 53.9 ± 26.0 NS
Mean nocturnal rise
31.5 ± 11.0 37.2 ± 12.8 NS
(onset to 0300h (pg/ml)
AUC (onset to 0300h)
173.5 ± 138.4 205.3 ± 137.8 0.15
(pg/ml x h)
NS: Not signi cant; AUC: Area under the curve
Table 2. Sleep recording data after pyridoxine or placebo adminis-
tration in normal men (Data are mean ± SD)
Sleep parameters Pyridoxine Placebo P value
Total recording time (h:min) 1:50 ± 0:03 1:44 ± 0:07 0.08
Actual sleep time (h: min) 1:23 ± 0:11 1:19 ± 0:16 NS
Sleep ef ciency (%) 69.4 ± 9.7 66.0 ± 12.5 NS
Sleep latency (minutes) 10 ± 3 15 ± 8 0.09
REM latency (minutes) 37 ± 30 49 ± 8 NS
Stage 1 (%) 4.5 ± 1.7 3.5 ± 2.9 NS
Stage 2 (%) 53.6 ± 9.4 46.3 ± 7.5 NS
Stage ¾ (%) 8,9 ± 7.7 16.7 ± 14.4 NS
REM (%) 12.4 ± 7.7 9.3 ± 10.7 NS
NS: not signi cant
Figure 1. Serum melatonin levels and core body temperature values after pyridoxine and
placebo administration in normal men.
Rafael Luboshitzky, U. Ophir, Rachel Nave, Rachel Epstein, Zila Shen-Orr & Paula Herer
In the present study we determined the effect of a
single oral dose of 100 mg pyridoxine given in the af-
ternoon on serum melatonin levels, core body tempera-
ture and sleep pattern in normal adult men. We used a
calculated dose related to body weight (1.5 mg/kg body
weight), which is much higher than the daily basal re-
quirement of pyridoxine, taking in account the intes-
tinal absorption and liver metabolism [21]. The three
circadian rhythms examined revealed similar results
after pyridoxine and placebo. Animal studies revealed
that in pyridoxine de cient rats, melatonin synthesis
was reduced and the addition of pyridoxine restored
the levels of pineal melatonin to values observed in
control animals [22]. Also, the administration of mela-
tonin increased brain pyridoxal phosphokinase activity
[23]. A mild hypothermia was observed in female rats
during pyridoxine treatment. The hypothermic effect
appeared by day 3 of treatment. The reduction in core
body temperature was greater early in the day [24].
It is not clear whether the hypothermic effect of pyri-
doxine was mediated through the release of melatonin,
as melatonin levels were not determined in this study.
Positive immunohistochemical staining for pyridoxine-
5-phosphate oxidase was demonstrated in mammalian
hypothalamic paraventricular nucleus [25]. Also, pos-
itive staining to brain pyridoxal kinase was demon-
strated in human brain [26].
The effect of pyridoxine on dreaming was investi-
gated in adult men treated with 100 mg pyridoxine or
placebo prior to bedtime for 4 consecutive days. The
data suggested that pyridoxine may act by increasing
cortical arousal during periods of rapid eye movement
(REM) sleep. The authors suggested that this action of
pyridoxine might result from the conversion of trypto-
phan to serotonin [27].
Pharmacological doses of pyridoxine signi cantly
decreased pituitary hormone levels [3]. Others failed to
observe any effect of acute or chronic pyridoxine treat-
ment on anterior pituitary hormones in amenorrheic
women [28]. In young children and infants single IV
dose of pyridoxine given at 21:00h, but not when given
at 09:00h, signi cantly increased serum melatonin lev-
els three hours later. In this study, only two blood sam-
ples were obtained from each subject for the determi-
nation of melatonin levels [29]. These ndings are in
contrast with our results and may be due to differences
in the populations studied, the route and dose of pyri-
doxine administered and frequency of blood sampling.
Rat brain serotonin levels were increased after tryp-
tophan load. Coadministration of pyridoxine, signif-
icantly increased serotonin levels in the hypothala-
mus when tryptophan intake was in excess, but not
with a diet of basal tryptophan requirement [30]. Oral
L-5-hydroxytryptophan administered to normal chil-
dren in the late evening hours signi cantly increased
serum melatonin levels [29].
In our study, oral administration of pyridoxine may
be associated with retarded absorption and hepatic me-
tabolism of pyridoxine, which may alter the available
dose of the vitamin in the circulation [31]. Consider-
ing that our subjects were in good health and probably
were not consuming tryptophan or pyridoxine in ex-
cess, which may account for the lack of effect of pyri-
doxine on melatonin levels in the current study.
Our data suggest that acute oral administration of
100 mg pyridoxine given in the afternoon to normal
adult men has no immediate effect on serum melatonin
levels, core body temperature or sleep quality.
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... In a study of 12 healthy men by Luboshitzky et al. (2002) at 5 p.m., half of them were given 100 mg of vitamin B6 and the other half were given placebo. At about 10 p.m. in both groups receiving the drug and placebo, the serum level of melatonin increased without any statistical difference between the two groups. ...
... At about 10 p.m. in both groups receiving the drug and placebo, the serum level of melatonin increased without any statistical difference between the two groups. Also, the amount of sleep pattern between the two groups was the same (Luboshitzky et al., 2002). ...
Full-text available
Objective Vitamin B6 has been linked to a variety of probable roles, including anti‐inflammatory, homocysteine‐lowering, serotonin‐regulating, and dopamine‐lowering. In this study, we investigated the possible effect of vitamin B6 on bipolar disorder in manic episode with psychotic feature in a placebo‐controlled double‐blind clinical trial in a psychiatric hospital. Methods This study was performed on 50 patients who were equally divided into two groups (each group included 25 patients) using 80 mg of vitamin B6 daily or placebo. At the beginning and end of the study, they were evaluated for lab tests, inflammatory biomarkers and level of blood homocysteine. Also, at the baseline and in weeks 2, 4, and 8, they were evaluated based on the anthropometric measurements, score obtained from the Young Mania Questionnaire, Mini‐Mental State Examination (MMSE), and the Pittsburgh Sleep Questionnaire. Results Accordingly, based on Yang Mania scoring scale, no significant difference was observed between the two groups receiving vitamin B6 and placebo (22.68 ± 5.39 vs. 21.80 ± 5.39 [p‐value = .51]). Based on MMSE, significant improvement in cognitive status was obtained in group placebo compared to vitamin B6 group (25.24 ± 1.96 vs. 24.40 ± 3.25, respectively [p‐value = .01]). At the Pittsburg scale (total, there was no statistically significant difference between the two groups receiving vitamin B6 and placebo (1.04 ± 0.20 vs. 0.48 ± 0.50 [p‐value = .23]). Additionally, no significant difference was observed between the two groups regarding the anthropometric status. Conclusions According to this study, the daily dose of 80 mg of vitamin B6 for 8 weeks in patients with bipolar disorder in the manic episode with psychotic feature treated daily with lithium, was not associated with a significant improvement in mood status compared to the control–placebo group. It is recommended to perform similar studies in a multi‐center manner with a larger sample size and longer duration.
... Альфа казозепін входить до дієтичної добавки Фломма, що містить у своєму складі, крім альфа казозепіну (Lactium ® ), вітамін В6. Вітамін В6 -кофактор у синтезі ГАМК, норадреналіну, дофаміну; необхідний для біо синтезу мелатоніну; бере участь у регуляції сну і в синтезі серотоніну з триптофану [22], в обміні метіоніну, цистеїну та інших аміно кислот. ...
... За даними літератури, застосування піри доксину перед сном має дозозалежний ефект на поліпшення яскравості сновидінь і здат ність до запам'ятовування снів [22]. У нещо давньому рандомізованому подвійному сліпо му плацебо контрольованому дослідженні, проведеному в Австралії [1], що стосувалося впливу на сновидіння й сон застосування 240 мг вітаміну В6 (піридоксину гідрохлориду) перед сном протягом 5 діб поспіль, виявлено, що вітамін В6 суттєво збільшує кількість сновидінь, дещо впливає на яскра вість і колір сну та суттєво не впливає на інші показники, пов'язані зі сном. ...
Узагальнено дані літератури з використання альфа-казозепіну та його комбінації з вітаміном В6 у клінічній практиці. Установлено, що властивості альфа-казозепіну близькі до властивостей сімейства бензодіазепінів, за винятком таких супутніх побічних ефектів, як звикання або седація, тому останнім часом альфа-казозепін частіше застосовують як дієтичну добавку для поліпшення сну і для усунення стресових розладів. Анксіолітичні ефекти альфа-казозепіну протягом останніх 20 років підтверджені в багатьох дослідженнях. Встановлено, що альфа-казозепін впливає на сон, модулюючи його архітектуру, але практично не має седативного ефекту, що робить його схожим на мелатонін. Вплив альфа-казозепіну на сон пов'язаний із рецепторами ГАМК. Виявлено, що при транспорті пептиду через гемато-енцефалічний бар'єр виділяється С-кінцевий залишок триптофану, попередника серотоніну, що є важливим нейромедіатором у регуляції настрою та ситості. Доведено безпосередню модуляцію альфа-казозепіном рецепторів ГАМК, у тому числі в нейронах гіпоталамусу. За результатами клінічних випробувань, альфа-казозепін позитивно впливає як на фізичну, так і на психологічну симптоматику тривожності. Показано, що застосування альфа-казозепіну сприяє швидшому відновленню після стресової реакції, що проявляється меншими показниками артеріального тиску і частоти серцевих скорочень у періоді релаксації (після стресу) порівняно з періодом відпочинку (до індукції стресу). Отже, анксіолітичні пептиди, отримані з молока, є перспективними в застосуванні при широкому колі функціональних розладів нервової системи, порушеннях сну, тривожних станах, у комплексному лікування пацієнтів з артеріальними дистоніями, у тому числі в дитячому віці. Заслуговує на увагу застосування комбінації альфа(казозепіну (Lactium®) та вітаміну В6, у тому числі в дітей, оскільки така комбінація сприяє гарному засвоєнню препарату і позитивному впливу на діяльність нервової системи. Автори заявляють про відсутність конфлікту інтересів.
... Pyridoxine supplementation has been reported to increase REM sleep and dream recall, however, the information on whether sleep quality is improved is limited. A randomized, double-blind, placebo-controlled study in healthy men (n = 12) by Luboshitzky et al. (2002) reported no effect on polysomnographic sleep recordings or melatonin secretion following evening treatment with 100 mg oral pyridoxine [54]. Participants supplemented with pyridoxine spent 33% more time in REM sleep than the placebo group, although this was reported as not statistically significant. ...
... Pyridoxine supplementation has been reported to increase REM sleep and dream recall, however, the information on whether sleep quality is improved is limited. A randomized, double-blind, placebo-controlled study in healthy men (n = 12) by Luboshitzky et al. (2002) reported no effect on polysomnographic sleep recordings or melatonin secretion following evening treatment with 100 mg oral pyridoxine [54]. Participants supplemented with pyridoxine spent 33% more time in REM sleep than the placebo group, although this was reported as not statistically significant. ...
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Functional beverages can be a valuable component of the human diet with the ability to not only provide essential hydration but to deliver important bioactive compounds that can contribute to chronic disease treatment and prevention. One area of the functional beverage market that has seen an increase in demand in recent years are beverages that promote relaxation and sleep. Sleep is an essential biological process, with optimal sleep being defined as one of adequate duration, quality and timing. It is regulated by a number of neurotransmitters which are, in turn, regulated by dietary intake of essential bioactive compounds. This narrative review aimed to evaluate the latest evidence of the sleep promoting properties of a selection of bioactive compounds (such as L-theanine and L-tryptophan) for the development of a functional beverage to improve sleep quality; and the effectiveness of traditional sleep promoting beverages (such as milk and chamomile). Overall, the bioactive compounds identified in this review, play essential roles in the synthesis and regulation of important neurotransmitters involved in the sleep-wake cycle. There is also significant potential for their inclusion in a number of functional beverages as the main ingredient on their own or in combination. Future studies should consider dosage; interactions with the beverage matrix, medications and other nutraceuticals; bioavailability during storage and following ingestion; as well as the sensory profile of the developed beverages, among others, when determining their effectiveness in a functional beverage to improve sleep quality.
... The results of another intervention study also showed that the vitamin B6-containing complex did not significantly improve sleep compared with the control group [41]. Furthermore, a study suggested that taking pyridoxine had no effect on melatonin secretion in men [53]. The reason for the inconsistent results may be the different target populations and sample sizes of the studies. ...
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The evidence on the relationship of pyridoxal 5′-phosphate (PLP) with sleep-related problems is limited and controversial. Notably, there is a lack of studies on the general population and studies of the dose–response relationship. Therefore, we conducted a cross-sectional study to examine the associations between serum PLP concentration and sleep-related problems (sleep quality and sleep duration) in adults, using the data of the National Health and Nutrition Examination Survey 2005–2010. High-performance liquid chromatography (HPLC) was used to test PLP in blood samples. Sleep quality and sleep duration were based on self-reported data, with sleep quality categorized as sleep disorder, trouble falling asleep, waking up during the night, and daytime sleepiness. The primary analyses utilized logistic regression models and restricted cubic spline. Compared with the first quartile (Q1), the odds ratios (ORs) and 95% confidence intervals (CIs) of daytime sleepiness for the Q2 and Q3 of serum PLP concentrations were 0.76 (0.59–0.99) and 0.78 (0.62–0.98), respectively. The relationship was only significant for males. Furthermore, a non-linear dose–response relationship was observed between serum PLP concentration and the risk of daytime sleepiness. Compared with the normal sleep duration group, serum PLP concentrations were negatively associated with the risks of very short, short, and long sleep duration, with relative risk ratios (RRRs) of 0.58 (0.43–0.81) (Q4), 0.71 (0.61–0.83) (Q4) and 0.62 (0.34–0.94) (Q3), respectively. The average serum PLP concentrations were higher in people with normal sleep duration, suggesting a non-linear dose–response relationship. Our study indicated that serum PLP concentrations were negatively associated with daytime sleepiness, and this association may only exist in males. Moreover, it was also inversely related to abnormal sleep duration (very short, short, long) compared to normal sleep duration.
... 12 Some studies have reported that Vitamin B6 does not affect the secretion of melatonin in adults. 13 However, it is observed that injections of vitamin B6 strengthen the biosynthesis of melatonin. 14 Tetrahydrobiopterin serves as a cofactor in the processes by which amino acids convert to monoamine neurotransmitters, including adrenaline, serotonin, and melatonin. ...
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Studies have shown that despite the decreasing mortality rates of kidney cancer patients, its incidence is increasing. Therefore, a comprehensive re-evaluation of treatment options is necessary to provide appropriate treatments for the increasing number of patients. Moreover, the side effects caused by surgery, which is the main treatment of this disease, may lead to higher morbidity rates. Consequently, new safer approaches must be examined and considered. Major advancements have been made in the field of targeted agents as well as treatments based on immunotherapy since renal cell carcinoma (RCC) does not respond well to chemotherapy. While the therapeutic options for this cancer are increasing, the resulting complexity of selecting the best strategy for treating the patients is daunting. Moreover, each therapeutic option must be evaluated concerning toxicity, cost, and clinical advantages. Several characteristics, which are beneficial for cancer therapies have been attributed to melatonin. For decades, investigations have explored the application of melatonin in the treatment of cancer; insufficient attention has been paid to this molecule at the clinical level. Melatonin plays a role in cancer therapy due to its anti-tumor effects as well as by enhancing the efficacy of other drugs as an adjuvant. In this review, we discuss different roles of melatonin in the treatment of kidney cancer. The studies concerned with the applications of melatonin as an adjuvant in the immunotherapy of patients with kidney cancer are summarized. Also, we highlight the apoptotic and anti-angiogenic effects of melatonin on renal cancer cells which are mediated by different molecules (e.g., HIF-1 and VEGF, ADAMTS1, and MMP-9) and signaling pathways (e.g., P56, P52, and JNK). Furthermore, we take a look into available data on melatonin's ability to reduce the toxicities caused by kidney carcinogens, including ochratoxin A, potassium bromate, and Fe-NTA.
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As interest in circadian rhythms and their effects continues to grow, there is an increasing need to perform circadian studies in humans. Although the constant routine is the gold standard for these studies, there are advantages to performing more naturalistic studies. Here, a review of protocols for such studies is provided along with sample inclusion and exclusion criteria. Sleep routines, drug use, shift work, and menstrual cycle are addressed as screening considerations. Regarding protocol, best practices for measuring melatonin, including light settings, posture, exercise, and dietary habits are described. The inclusion/exclusion recommendations and protocol guidelines are intended to reduce confounding variables in studies that do not involve the constant routine. Given practical limitations, a range of recommendations is provided from stringent to lenient. The scientific rationale behind these recommendations is discussed. However, where the science is equivocal, recommendations are based on empirical decisions made in previous studies. While not all of the recommendations listed may be practical in all research settings and with limited potential participants, the goal is to allow investigators to make well-informed decisions about their screening procedures and protocol techniques and to improve rigor and reproducibility, in line with the objectives of the National Institutes of Health.
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Vitamin B6 (vitB6) is a generic term that comprises six interconvertible pyridine compounds. These vitB6 compounds (also called vitamers) are pyridoxine (PN), pyridoxamine (PM), pyridoxal (PL) and their 5′-phosphorylated forms pyridoxine 5′-phosphate (PNP), pyridoxamine 5′-phosphate (PMP) and pyridoxal 5′-phosphate (PLP). VitB6 is an essential nutrient for all living organisms, but only microorganisms and plants can carry out de novo synthesis of this vitamin. Other organisms obtain vitB6 from dietary sources and interconvert its different forms according to their needs via a biochemical pathway known as the salvage pathway. PLP is the biologically active form of vitB6 which is important for maintaining the biochemical homeostasis of the body. In the human body, PLP serves as a cofactor for more than 140 enzymatic reactions, mainly associated with synthesis, degradation and interconversion of amino acids and neurotransmitter metabolism. PLP-dependent enzymes are also involved in various physiological processes, including biologically active amine biosynthesis, lipid metabolism, heme synthesis, nucleic acid synthesis, protein and polyamine synthesis and several other metabolic pathways. PLP is an important vitamer for normal brain function since it is required as a coenzyme for the synthesis of several neurotransmitters including D-serine, D-aspartate, L-glutamate, glycine, γ-aminobutyric acid (GABA), serotonin, epinephrine, norepinephrine, histamine and dopamine. Intracellular levels of PLP are tightly regulated and conditions that disrupt this homeostatic regulation can cause disease. In humans, genetic and dietary (intake of high doses of vitB6) conditions leading to increase in PLP levels is known to cause motor and sensory neuropathies. Deficiency of PLP in the cell is also implicated in several diseases, the most notable example of which are the vitB6-dependent epileptic encephalopathies. VitB6-dependent epileptic encephalopathies (B6EEs) are a clinically and genetically heterogeneous group of rare inherited metabolic disorders. These debilitating conditions are characterized by recurrent seizures in the prenatal, neonatal, or postnatal period, which are typically resistant to conventional anticonvulsant treatment but are well-controlled by the administration of PN or PLP. In addition to seizures, children affected with B6EEs may also suffer from developmental and/or intellectual disabilities, along with structural brain abnormalities. Five main types of B6EEs are known to date, these are: PN-dependent epilepsy due to ALDH7A1 (antiquitin) deficiency (PDE-ALDH7A1) (MIM: 266100), hyperprolinemia type 2 (MIM: 239500), PLP-dependent epilepsy due to PNPO deficiency (MIM: 610090), hypophosphatasia (MIM: 241500) and PLPBP deficiency (MIM: 617290). This chapter provides a review of vitB6 and its different vitamers, their absorption and metabolic pathways in the human body, the diverse physiological roles of vitB6, PLP homeostasis and its importance for human health. Finally, the chapter reviews the inherited neurological disorders affecting PLP homeostasis with a special focus on vitB6-dependent epileptic encephalopathies (B6EEs), their different subtypes, the pathophysiological mechanism underlying each type, clinical and biochemical features and current treatment strategies.
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Background and aim: Melatonin is an immune modulator that displays both pro- and anti-inflammatory properties. The aim of this study was to review the effect of melatonin supplementation on muscle injury, inflammation, and oxidative stress in intense exercise. The aim of this study was to review the effect of melatonin supplementation on muscle injury, inflammation, and oxidative stress in intense exercise. Methods: In this study, articles were searched in specialized databases, and all available resources were provided using appropriate keywords. Results: Studies have shown that exercise leads to oxidative stress and inflammation, which is directly related to the intensity of activity; Moderate-intensity exercise stimulates adaptive reactions, but strenuous exercise, which significantly increases the production of reactive oxygen species (ROS) and oxidative stress, may cause harm to athletes. The results showed that melatonin supplementation in athletes increased growth hormone, catalase (CAT), glutathione peroxidase (GPx), total antioxidant status (TAS), and decreased levels of cytokines TNFα and IL-6. Conclusion: The present study showed that melatonin oral supplementation in high-intensity exercise is effective in reducing oxidative stress (reducing fat peroxidation, with a significant increase in antioxidant enzymes) that leads to cell preservation and tissue damage and also accelerates recovery. This information also shows that melatonin has strong protective effects, prevents the occurrence of excessive inflammatory mediators, and prevents the effects of multiple inflammatory cytokines. Keywords: Melatonin Oxidative Stress Intense Activity Inflammation Reactive Oxygen Species
One of the host risk factors involved in aging-related diseases is coupled with the reduction of endogenous melatonin (MLT) synthesis in the pineal gland. MLT is considered a well-known pleiotropic regulatory hormone to modulate a multitude of biological processes such as the regulation of circadian rhythm attended by potent anti-oxidant, anti-inflammatory, and anti-cancer properties. It has also been established that the microRNAs family, as non-coding mRNAs regulating post-transcriptional processes, also serve a crucial role to promote MLT-related advantageous effects in both experimental and clinical settings. Moreover, the anti-aging impact of MLT and miRNAs participation jointly are of particular interest, recently. In this review, we aimed to scrutinize recent advances concerning the therapeutic implications of MLT, particularly in the brain tissue in the face of aging. We also assessed the possible interplay between microRNAs and MLT, which could be considered a therapeutic strategy to slow down the aging process in the nervous system.
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Objectives: To review whether there is evidence in favour of using melatonin as a skin photoprotective agent. Methods: Search in the databases National Guideline Clearinghouse, NICE Guidelines Finder, The Cochrane Library and MEDLINE/PubMed, of Portuguese Health Ministry’s Direção-Geral da Saúde clinical guidelines (NOC), systematic reviews (RS), meta-analyses (MA) and randomized controlled trials (ECA), published between January 1998 and January 2018, using the MeSH terms ‘skin erythema’, ‘skin aging’, ‘melatonin’ and ‘stress’. The search was limited to articles written in English and Portuguese. Results: Seven ECA from an initial survey of 93 articles were included. No RS, MA or NOC were found on the subject. The selected articles demonstrated the efficacy of the use of melatonin in the reduction of post-exposure cutaneous erythema, and with a photoprotective effect, if used before sun exposure or ultraviolet radiation; if used later, its effect was null. Conclusions: Melatonin therapy has, in the short term, a photoprotective effect. Studies with larger samples and with a longer follow-up period are necessary to test for the effectiveness and safety of melatonin in the long-term.
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Total activity (pyridoxal 5*-phosphate (PLP) added in the assay) of hepatic tyrosine aminotransferase (TAT) measured in cats at 0300, 0900, 1500 and 2100h was 10.3 {1.1, 14.0 { 0.7, 9.8 { 1.3 and 11.0 { 0.7 nkat/g liver, indicating little diurnal variation. Activity after 18 h of food deprivation was 10.0 { 0.3 nkat/g liver, also not different from cats that were eating ad libitum. These findings support the idea that cats have only limited changes in the activity of hepatic TAT compared with rats. Total TAT activity was measured in cats fed high protein (550 g/kg) and low protein (180 g/kg) diets for 4 wk. Cats fed a high protein diet had activities significantly higher (about twice) than cats fed the low protein diet. Hepatic TAT activity of vitamin B-6-deficient cats (diet without pyridoxine for 9 wk) was compared with cats given the same diet with 8 mg pyridoxine/kg. Total hepatic TAT activity in deficient cats was significantly (Põ 0.05) lower per gram soluble or total protein (but not per gram liver) than control cats; holoenzyme activity and percentage of active enzyme in deficient cats were also significantly lower by 75 and 64%, respectively. The apparent Km of TAT from cats for tyrosine (2.1 mmol/L) was similar to that for rats (1.9 mmol/L), but higher for PLP in cats (0.16 mmol/L) than rats (0.034 mmol/L). Part of the reason for the higher plasma tyrosine in vitamin B-6-deficient cats than rats is the higher Km of TAT for PLP in cats than rats. J. Nutr. 128: 1995-2000, 1998.
Twelve young adults were treated with either melatonin, 3 mg or 6 mg, or placebo, at two different times before an early evening nap (18.00–20.00 h) according to a balanced double-blind Latin square design. Polysomnographic monitoring revealed that both dosages of melatonin significantly shortened sleep latency and increased total sleep time in comparison to placebo, irrespective of the time of administration. Subjects also tended to assess their sleep as ‘deeper’ after melatonin treatment. Based on previous data and the present results, it was concluded that exogenous melatonin exerts hypnotic effects only when circulating levels of endogenous melatonin are low.
In previous studies, we found that many totally blind people have free-running melatonin rhythms, but that free-running melatonin rhythms were not necessarily associated with periodic insomnia and daytime sleepiness. Thus, it was not clear if the circadian sleep propensity rhythm was free-running with the other circadian rhythms. In the present study, we report that the sleep propensity rhythm (as defined by an ultrashort sleep-wake schedule) free-ran with the melatonin, temperature and cortisol rhythms in a 44-year-old totally blind man even though he maintained a conventional sleep schedule and did not complain of clinically significant insomnia or excessive daytime sleepiness.
Early morning rectal body temperature is lowest when melatonin levels are highest in humans. Although pharmacological doses of melatonin are hypothermic in humans, the relationship between endogenous melatonin and temperature level has not been investigated. We measured rectal body temperature in nine normal men whose melatonin levels were suppressed by all-night sleep deprivation in bright light and compared values with those seen in sleep in the dark, sleep deprivation in dim light (to control for the stimulatory effect of wakefulness on temperature), and sleep deprivation in bright light with an infusion of exogenous melatonin that replicated endogenous levels. Minimum rectal temperature, calculated from smoothed temperature data from 2300 to 0515 h, was greater in bright-light sleep deprivation, resulting in suppression of melatonin, than in conditions of sleep deprivation in dim light or sleep in the dark. An exogenous melatonin infusion in bright light returned the minimum temperature to that seen in dim-light sleep deprivation. A nonsignificant elevation in mean and minimum temperature was noted in all conditions of sleep deprivation relative to sleep. We conclude that melatonin secretion contributes to the lowering of core body temperature seen in the early morning in humans.
Pyridoxine deficiency causes physiologically significant decrease in brain serotonin (5-HT) due to decreased decarboxylation of 5-hydroxytryptophan (5-HTP). We have examined the effect of pyridoxine deficiency on indoleamine metabolism in the pineal gland, a tissue with high indoleamine turnover. Adult male Sprague-Dawley rats were fed either a pyridoxine-supplemented or pyridoxine-deficient diet for 8 weeks. Pyridoxine deficiency did not alter the pattern of circadian rhythm of pineal 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), N-acetylserotonin (NAS), and melatonin. However the levels of these compounds were significantly lower in the pineal glands of pyridoxine-deficient animals. Pineal 5-HTP levels were consistently higher in the pyridoxine-deficient animals and a conspicuous increase was noticed at 22.00 h. Increase in pineal NAS and melatonin levels caused by isoproterenol (5 mg/kg at 17.00 h) were significantly lower (P less than 0.05) in the pyridoxine-deficient animals. Treatment of pyridoxine-deficient rats with pyridoxine restored the levels of pineal 5-HT, 5-HIAA, NAS, and melatonin to values seen in pyridoxine-supplemented control animals. These results suggest that 5-HT availability could be an important factor in the regulation of the synthesis of pineal NAS and melatonin.
We studied the metabolic effects of high dietary intakes of pyridoxine and of the substrate-cofactor interaction between dietary histidine or tryptophan and pyridoxine in rat brain. In the substrate-cofactor interaction study, histamine and serotonin levels were determined in rats fed elevated or requirement levels of substrate (histidine: 0.3% and 0.8%, tryptophan: 0.15% and 0.6%) and excess or requirement levels of pyridoxine HCl (7 mg vs. 3,000 mg/kg). Excess pyridoxine intake caused a differential effect on brain histamine concentration--inhibitory with the requirement level of histidine (-29%), and stimulatory (+21%) with the elevated level of histidine. When dietary tryptophan was fed at the requirement level, excess pyridoxine caused essentially no changes in hypothalamic serotonin and 5HIAA (-2%, -2%). With elevated tryptophan intake, excess pyridoxine significantly increased serotonin and 5HIAA (+32%, +20%) in the hypothalamus. These results indicate a clear interaction between substrate and coenzyme precursor which influences brain metabolism of histamine and serotonin.
In order to assess the effect of pinealectomy (Px) on the diurnal rhythmicity of gamma-aminobutyric acid (GABA) high affinity binding to cerebral cortex membranes, groups of intact, Px or sham Px rats (subjected to surgery 15 days earlier) were killed at six different time intervals during the 24-hour cycle. GABA binding was estimated by Scatchard analysis of 3H-GABA binding to cerebral cortex membranes prepared from individual brains; only one type of binding site with dissociation constant (KD) about 20-50 nM and site number (Bmax) about 200-500 fmol/mg protein was apparent in the assay conditions employed. In intact and sham Px rats Bmax attained minimal values at night and increased during daylight. Px increased generally Bmax and disrupted its normal diurnal rhythmicity, a peak in Bmax being observed at midnight. A significant decrease of GABA high affinity binding affinity was detected at morning hours in intact rats and at late scotophase and morning hours in Px and sham Px rats. Bmax of GABA high affinity binding in Px rats attained maximal values by 5-10 days after surgery and decreased somewhat 5 days later. Sham Px rats exhibited a transient increase in Bmax up to 10 days after surgery, returning to normal values by the 15th day. Superior cervical ganglionectomy increased binding affinity up to 15 days after surgery without affecting Bmax. The minimal melatonin effective dose to counteract Px-induced increase of GABA high affinity binding was 25 micrograms/kg body weight when given 3 h before sacrifice. Melatonin activity on GABA binding did not depend upon a direct effect on the binding sites, as shown in vitro. These results suggest a link between pineal function, melatonin secretion and GABA receptor activity in rats.
Data from the long-term projects sponsored by the Food and Nutrition Board to determine the requirements for thiamin, riboflavin, niacin-tryptophan, and vitamin E are utilized to effect an opinion regarding the recommended dietary allowances for these vitamins. Based upon data obtained during these and subsequent research projects, comments on balance studies, changes in tissue lipids, and the requirements for vitamin B-6 are included. The possibility that antioxidants may have an effect on delaying oncogenesis is discussed.