1 s2.0 S1347861319305729 Main
1 s2.0 S1347861319305729 Main
1 s2.0 S1347861319305729 Main
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Abstract. Glycine is a non-essential amino acid that has indispensable roles in both excitatory
and inhibitory neurotransmission via N-methyl-D-aspartate type glutamate receptors and glycine
receptors, respectively. We recently reported that glycine ingestion before bedtime significantly
ameliorated subjective sleep quality in individuals with insomniac tendencies. Oral administration
of glycine to rats was found to induce a significant increase in the plasma and cerebrospinal fluid
glycine concentrations and a significant decrease in the core body temperature associated with an
increase in cutaneous blood flow. The decline in the core body temperature might be a mechanism
underlying glycine’s effect on sleep, as the onset of sleep is known to involve a decrease in the
core body temperature. Moreover, a low core body temperature is maintained during sleep in
humans. Pharmacological studies investigating the mechanisms of glycine on sleep were also
performed. In this review, we will describe both our recent findings regarding how and where
orally administered glycine acts and findings from our rat study and human trials.
Keywords: non-essential amino acid, blood–brain barrier, vasodilatation, core body temperature,
N-methyl-D-aspartate (NMDA) receptor
1. Introduction 2. Glycine
The importance of sleep has recently been emphasized Glycine is a non-essential amino acid and has the
throughout the world. Nonetheless, a meta-analysis has simplest molecular structure of all the amino acids. Ani-
revealed that approximately 30% of the general popula- mal cells obtain sufficient amounts of glycine by either
tion present with insomnia symptoms (1). Insomnia is de novo synthesis or through dietary proteins. Approxi-
known to induce cognitive inefficiency, sleepiness, mood mately 45 g of endogenous glycine is synthesized (6),
disruptions (2), impaired attention, and memory deficits and 3 – 5 g of glycine is taken up from the diet, daily in
(3). Thus, the amelioration of insomnia is very important humans.
for society. Endogenously synthesized glycine functions as an in-
We have recently found that glycine improves sleep hibitory neurotransmitter in the central nervous system
quality in humans who have repeated complains about via the glycine receptors (GlyRs) (7). In contrast, glycine
sleep (4, 5). This treatment is a novel approach to im- also acts as a co-agonist for the channel opening of the
prove sleep via the administration of an amino acid. The N-methyl-D-aspartate subtype of ionotropic glutamate
objectives of this review are to elucidate the effects of receptors (NMDARs) (8, 9). Glycine is also known as an
glycine on sleep improvement and describe the effects of anti-inflammatory agent that protects against disease
glycine in humans. states in animal models of ischemia–reperfusion, injury,
and transplantation (10). Moreover, glycine has been
reported to attenuate the increase in free fatty acids and
the accumulation of abdominal fat in sucrose-fed rats
(11).
*Corresponding author. [email protected] Given that glycine is often considered to be a biologi-
Published online in J-STAGE on January 27, 2012 (in advance) cally neutral molecule, it is used as an isonitrogenous
doi: 10.1254/jphs.11R04FM control in amino acid supplementation studies. In this
145
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This is an open access article under the CC BY-NC-ND License (http://creativecommons.org/licenses/by-nc-nd/).
146 M Bannai and N Kawai
context, we used glycine as a placebo in a human trial to We then performed a pharmacological study to identify
investigate the functions of other amino acids. The unex- the primary glycine binding receptor in the brain. Pre-
pected results of this human trial instigated the study of treatment with the NMDAR antagonists AP5 and
the effects of glycine on sleep. CGP78608 into the lateral ventricle attenuated the vaso-
dilatation induced by glycine, whereas pretreatment with
3. The pharmacokinetics of glycine the GlyR antagonist strychnine did not. In addition, a
single treatment of the NMDAR glycine site agonist D-
To investigate the effects of glycine on improving serine resulted in a significant increase in subcutaneous
sleep, we first examined the permeability of the blood– blood flow. Taken together, these results suggest that
brain barrier to externally administered glycine in rats administered glycine primarily acts on NMDARs.
(12). The concentration–time curve showed that the oral Next, we investigated the effect of glycine on several
administration of 2 g/kg glycine increased the plasma hypothalamic nuclei to identify the primary action site,
glycine concentration to 5371 ± 507 μΜ (Cmax), which as the hypothalamus is the center for both sleep and body
was 13-fold higher than that of control animals given temperature regulation. After unilateral or bilateral
vehicle alone (vehicle controls) at 30 min (Tmax) after microinjection into the medial preoptic area (mPOA, the
administration. In the cerebrospinal fluid, the glycine center of thermoregulation), dorsal subparaventricular
levels reached 52.7 ± 4.4 μΜ (Cmax), which was 6-fold zone (dSPZ, a regulator of thermogenesis and sleep), or
higher than that of the control animals at 30 min (Tmax). the suprachiasmatic nucleus (SCN, the center of the cir-
The cerebrospinal fluid (CSF) concentration of glycine cadian rhythm), vasodilatation was only present when
has been shown to be higher than the ED50 of NMDARs glycine was bilaterally injected into the SCN, suggesting
(100 – 300 nM) and lower than that of GlyRs (90 – 100 that the bilateral action of the SCN is necessary for in-
μM) (13), suggesting that orally administered glycine ducing vasodilatation. Together, our findings indicate
directly acts on NMDARs. In our study, the cortical that orally administered glycine passes into the brain
levels of glycine reached 1376 ± 30 pmol/mg wet tissue passively and acts on NMDARs in the SCN, resulting in
(Cmax), which was 2-fold higher than that observed in the vasodilatation and, subsequently, a decreased CBT.
vehicle controls after 4 h (Tmax). For a detailed analysis, The effect of glycine on sleep in rats was also investi-
we investigated the glycine uptake into the brain using gated using electroencephalogram/electromyogram
the brain uptake index (BUI) method (14, 15). The brain (EEG/EMG) recordings. Glycine (2 g/kg) significantly
uptake of glycine varied with respect to the injected increased non-REM (NREM) sleep and reduced wake
quantities of glycine, ranging from 0.67 to 2.5 mmol/kg. state in sleep-disturbed rats after 2 h of oral administra-
The calculated BUIs in the range were between 2.6% and tion. These studies in rats revealed that glycine can im-
9.0%, and these values were almost stable. The BUIs of prove sleep by decreasing CBT.
the essential amino acids, which are transported by a Finally, we have previously reported that the oral ad-
specific transporter (16), have been shown to decrease ministration of glycine increases extracellular serotonin
according to their injected quantities (17). A high dose of release in the rat prefrontal cortex (23). This release of
the essential amino acids would saturate their specific serotonin should indirectly support the glycine-mediated
transporters, resulting in a lower BUI. Taken together, improvement in sleep quality.
these observations indicate that glycine passively dif-
fuses across the blood–brain barrier by nonspecific 5. Glycine and sleep in humans
transportation.
We have previously reported three human volunteer
4. The pharmacological effects of glycine on sleep in studies to subjectively assess the effect of glycine on
rats sleep. Individuals with continuous complaints about the
quality of their sleep were recruited and given either 3 g
Sleep and core body temperature (CBT) are signifi- of glycine or a placebo before bedtime. In the first study
cantly correlated. CBT has a circadian oscillation; i.e., it (4), a randomized double-blinded crossover trial, 19 fe-
drops at the onset of sleep (18, 19), continues to decrease male volunteers (24 – 53 years of age; average, 31.1
during sleep (20) and gradually rises as a person wakes years) participated. All of the subjects had complained
(21). We investigated the effects of glycine on CBT in about their sleep quality. Their Pittsburgh Sleep Quality
rats (22). A total of 2 g/kg of orally administered glycine Index (PSQI) scores were 6 or greater, indicating that the
significantly decreased CBT in addition to causing vaso- subjects had continuously experienced unsatisfactory
dilatation. Furthermore, intracerebroventricular adminis- sleep. The subjective quality of sleep was evaluated us-
tration of glycine (130 nmol) also induced vasodilatation. ing the St. Mary’s Hospital (SMH) Sleep Questionnaire
Effects of Glycine on Sleep 147