Administration Of L-serine Research Articles

A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations.

Mutations in the SLC1A4 transporter lead to neurodevelopmental impairments, spastic tetraplegia, thin corpus callosum, and microcephaly in children. SLC1A4 catalyzes obligatory amino acid exchange between neutral amino acids, but the physiopathology of SLC1A4 disease mutations and progressive microcephaly remain unclear. Here, we examined the phenotype and metabolic profile of three Slc1a4 mouse models, including a constitutive Slc1a4-KO mouse, a knock-in mouse with the major human Slc1a4 mutation (Slc1a4-K256E), and a selective knockout of Slc1a4 in brain endothelial cells (Slc1a4tie2-cre). We show that Slc1a4 is a bona fide L-serine transporter at the BBB and that acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain. This results in microcephaly associated with decreased L-serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids in the brain, neurodegeneration, synaptic and mitochondrial abnormalities, and behavioral impairments. Prenatal and early postnatal oral administration of L-serine at levels that replenish the serine pool in the brain rescued the observed biochemical and behavioral changes. Administration of L-serine till the second postnatal week also normalized brain weight in Slc1a4-E256 K mice. Our observations suggest that the transport of "non-essential" amino acids from the blood through the BBB is at least as important as that of essential amino acids for brain metabolism and development. We proposed that SLC1A4 mutations cause a BBB aminoacidopathy with deficits in serine import across the BBB required for optimal brain growth and leads to a metabolic microcephaly, which may be amenable to treatment with L-serine.

Impairment of serine transport across the blood–brain barrier by deletion of Slc38a5 causes developmental delay and motor dysfunction

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. Slc38a5-KO pups exhibit motor impairments that are affected by the administration of L-serine at concentrations that replenish the serine pool in the brain. Our results highlight a critical role of Slc38a5 in supplying L-serine via the BBB for proper brain development.

Twelve Weeks of Oral L-Serine Supplementation Improves Glucose Tolerance, Reduces Visceral Fat Pads, and Reverses the mRNA Overexpression of Renal Injury Markers KIM-1, IL-6, and TNF-α in a Mouse Model of Obesity

Comorbidities associated with obesity, including diabetes and kidney diseases, greatly increase mortality rates and healthcare costs in obese patients. Studies in animal models and clinical trials have demonstrated that L-serine supplementation is a safe and effective therapeutic approach that ameliorates the consequences of obesity. However, little is known about the effects of L-Serine supplementation following high-fat diet (HFD) consumption and its role in the mRNA expression of markers of kidney injury. We provide a descriptive action by which L-serine administration ameliorated the consequences of HFD consumption in relation to weight loss, glucose homeostasis as well as renal mRNA expression of markers of kidney injury. Our results indicated that L-Serine supplementation in drinking water (1%, ad libitum for 12 weeks) in male C57BL/6J mice promoted a significant reduction in body weight, visceral adipose mass (epididymal and retroperitoneal fat pads) as well as blood glucose levels in mice consuming a HFD. In addition, the amino acid significantly reduced the mRNA expression of the Kidney Injury Marker 1 (KIM-1), P2Y purinoceptor 1 (P2RY1), as well as pro-inflammatory cytokines (IL-6 and TNFα). L-serine administration had no effect on mice consuming a standard chow diet. Collectively, our findings suggest that L-serine is an effective compound for long-term use in animal models and that it ameliorates the metabolic consequences of HFD consumption and reduces the elevated levels of renal pro-inflammatory cytokines occurring in obesity.

Effect of L-serine on oxidative stress markers in the kidney of streptozotocin-induced diabetic mice.

Oxidative stress is critical in the occurrence and development of diabetes and its related complications. L-serine has recently been shown to reduce oxidative stress, the incidence of autoimmune diabetes and improve glucose homeostasis. The aim of this study was to investigate the effects of daily L-serine administration on blood glucose, renal function and oxidative stress markers in the kidney of streptozotocin-induced diabetic mice. Eighteen C57BL/6 male mice were randomly divided into three groups (n = 6 per group). Streptozotocin was used to induce diabetes and a group of diabetic mice was treated with 280mg/day of L-serine dissolved in drinking water for 4weeks. The level of blood glucose, biochemical markers of renal function (total protein, urea, creatinine and albumin) and oxidative stress markers (protein carbonyls, malondialdehyde, glutathione peroxidase, superoxide dismutase and catalase) were measured using spectrophotometry. The results indicated that L-serine significantly decreased the glucose level in diabetic mice (188.6 ± 22.69mg/dL, P = 0.02). Moreover, treatment of diabetic mice with L-serine reduced protein carbonyls (3.249 ± 0.9165nmol/mg protein, P < 0.05) and malondialdehyde levels (1.891 ± 0.7696μM/mg protein, P = 0.051). However, L-serine showed no significant effects on renal function, and a slight reduction in histopathological changes was observed in mice receiving L-serine. This study revealed that L-serine effectively ameliorates oxidative stress in kidney tissue and reduces the blood glucose concentration in diabetic mice.

L-serine modulates activities of antioxidant enzymes and behavioral responses in broiler chickens subjected to feed restriction during the hot-dry season

The aim of the study was to evaluate the effects of L-serine on catalase and glutathione peroxidase activities; latency, rest, number of lines crossed, attempts at jumping, vocalization, defecation, preening rate and tonic immobility of broiler chickens subjected to feed restriction during the hot-dry season. Broiler chicks (n =120) were divided into four groups of 30 each: Group A: feed restriction (FR); Group B: feed restriction + L-serine (FR + L-serine); Group C: feed ad libitum (AL); and Group D: feed ad libitum + L-serine (FR + L-serine). L-serine (200 mg/kg) was administered for 14 days orally from one-day old. Broiler chickens were subjected to 20%-feed restriction from day 7-14 of rearing. The temperature-humidity index recorded from the study period was 30.88 ± 0.81, indicating the chickens were subjected to environmental heat stress. At weeks 3, 4 and 5, serum catalase and glutathione peroxidase activities were evaluated. Tonic immobility and Open-field responses were assessed at weeks 4 and 5. Activities of catalase and glutathione peroxidase increased (P < 0.05) in FR + L-serine and AL + L-serine broiler chickens, compared to FR and AL broiler chickens. Latency duration, and rest and frequency of preening increased (P < 0.05) in FR and AL broiler chickens, compared to FR + L-serine and AL + L-serine broiler chickens. Tonic immobility decreased significantly (P < 0.05) in the following order: AL > FR > AL + L-serine > FR + L-serine broiler chickens. The results show that feed restriction and/or L-serine ameliorated the risk of adverse effects of environmental heat stress by increasing catalase and glutathione peroxidase activities; and by decreasing duration of rest, preening frequency, latency of movement and tonic immobility. In conclusion, L-serine administration and feed restriction, particularly in combination, alleviated the adverse heat stress-induced behavioral responses partly by enhancing activities of catalase and glutathione peroxidase.

L-Serine Influences Epigenetic Modifications to Improve Cognition and Behaviors in Growth Hormone-Releasing Hormone Knockout Mice.

Neurodegenerative diseases feature changes in cognition, and anxiety-like and autism-like behaviors, which are associated with epigenetic alterations such as DNA methylation and histone modifications. The amino acid L-serine has been shown to have beneficial effects on neurological symptoms. Here, we found that growth hormone-releasing hormone knockout (GHRH-KO) mice, a GH-deficiency mouse model characterized by extended lifespan and enhanced insulin sensitivity, showed a lower anxiety symptom and impairment of short-term object recognition memory and autism-like behaviors. Interestingly, L-serine administration exerted anxiolytic effects in mice and ameliorated the behavioral deficits in GHRH-KO. L-serine treatment upregulated histone epigenetic markers of H3K4me, H3K9ac, H3K14ac and H3K18ac in the hippocampus and H3K4me in the cerebral cortex in both GHRH-KO mice and wild type controls. L-serine-modulated epigenetic marker changes, in turn, were found to regulate mRNA expression of BDNF, grm3, foxp1, shank3, auts2 and marcksl1, which are involved in anxiety-, cognitive- and autism-like behaviors. Our study provides a novel insight into the beneficial effects of L-serine intervention on neuropsychological impairments.

Effects of L-serine administration on meat quality, characteristics and mineral content of tibia bone in heat-stressed broiler

in heat-stressed broiler chickens. One hundred and twenty broiler chicks were allocated into four groups of 30 each. Group A (feed restriction), Group B (feed restriction + L-serine), Group C (ad libitum) and Group D (ad libitum + L-serine). Feed restriction (20%) was implemented on days 7–14, and L-serine (200 mg/kg) was provided orally from days 1–14. Seven broiler chickens were slaughtered from each group at 35 days old to determine meat drip loss, cooking loss and pH; and tibia bone weight, length, diameter, weight/length index, robusticity index, strength and proximate analysis. Serum samples were harvested for the determination of calcium and phosphorus concentrations. Temperature-humidity index in the pen (28.72 - 32.90) was above the thermoneutral zone indicating heat stress. The drip loss and cooking loss were lower in FR + L-serine and AL + L-serine groups compared to the controls. The tibia bone weight, length, weight/length index and breaking force were higher (P &lt; 0.05) in FR + L-serine and AL + L-serine groups compared to the controls. The percentage composition of ash, calcium and phosphorus was relatively high in L-serine-administered groups. In conclusion, L-serine improved meat quality and tibia bone characteristics in broiler chickens exposed to heat stress

INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.

Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

Validating the inhibitory effects of d- and l-serine on the enzyme activity of d-3-phosphoglycerate dehydrogenases that are purified from Pseudomonas aeruginosa, Escherichia coli and human colon

BackgroundWe previously demonstrated that the serA gene is associated with bacterial pathogenicity, including bacterial penetration through the Caco-2 cell monolayers, bacterial motility, bacterial adherence, and fly mortality. l-Serine is known to inhibit the d-3-phosphoglycerate dehydrogenase (PGDH) activity of the SerA protein, and it significantly reduced the bacterial pathogenicity as described above. We also demonstrated that in a PGDH assay using crude extracts isolated from overnight cultures of E. coli overexpressing the P. aeruginosa serA gene, l-serine inhibited the PGDH activity of the SerA protein. The basal PGDH activity of the negative control strain was high, presumably due to contamination of unknown proteins in the crude extracts. Therefore, to further confirm the direct inhibition of PGDH activity of P. aeruginosa SerA by l-serine, we purified and characterized the PGDH from P. aeruginosa and compared it with the previously characterized PGDHs from E. coli, and the human colon as controls.ResultsOptimum pH and ionic strength of the purified PGDHs were different depending on the three species; optimal activity of P. aeruginosa PGDH was at pH 7.5 with 50–100 mM Tris–HCl, E. coli PGDH was at pH 8.5 with 100–200 mM Tris–HCl, and human PGDH was at pH 9.0 with 100–200 mM Tris–HCl. The addition of l-serine reduced the activity of PGDH from P. aeruginosa and E. coli, but not the PGDH from human colon. The median inhibitory concentration (IC50) of l-serine was 630 μM for P. aeruginosa and 250 μM for E. coli, while IC50 of d-serine was much higher than that of l-serine; 76 mM in P. aeruginosa PGDH and 45 mM in E. coli PGDH.ConclusionsThese results suggest that l-serine significantly repressed P. aeruginosa pathogenicity through direct inhibition of the PGDH activity, but was not able to inhibit the human PGDH activity. Oral administration of l-serine to compromised hosts might interfere with bacterial translocation and prevent gut-derived sepsis caused by P. aeruginosa through inhibition of the function of the serA gene product.

Long-Term l-Serine Administration Reduces Food Intake and Improves Oxidative Stress and Sirt1/NFκB Signaling in the Hypothalamus of Aging Mice.

Serine has recently been shown to reduce oxidative stress and inflammation, which, when occurring in the hypothalamus, contribute to age-related obesity. To explore whether long-term serine administration reduces oxidative stress and body weight in aging mice, various concentrations of l-serine dissolved in water were administered to 18-month-old C57BL/6J mice for 6 months. The results showed that the administration of 0.5% (w/v) l-serine significantly reduced food intake and body weight gain during the experiment. Moreover, the administration of 0.5% l-serine decreased the concentrations of leptin, malondialdehyde, interleukin-1β, and interleukin-6, while it increased those of superoxide dismutase and glutathione, in both the serum and hypothalamus. Reactive oxygen species and the activity of nicotinamide adenine dinucleotide phosphate oxidase were reduced in the hypothalamus of aging mice treated with l-serine as compared with untreated control mice. Additionally, the expression of the leptin receptor increased while the levels of neuropeptide Y and agouti-related protein decreased in mice that had been treated with 0.5% l-serine. The expression of Sirt1 and phosphorylated signal transducers and activators of transcription 3 (pSTAT3) increased, while that of phosphorylated NFκB decreased in the mice treated with 0.5% l-serine. These results indicated that long-term l-serine administration reduces body weight by decreasing orexigenic peptide expression and reduces oxidative stress and inflammation during aging in mice, possibly by modulating the Sirt1/NFκB pathway. Thus, l-serine has the potential to be used in the prevention of age-related obesity.

L-Serine Enhances Light-Induced Circadian Phase Resetting in Mice and Humans

Background: The circadian clock is modulated by the timing of ingestion or food composition, but the effects of specific nutrients are poorly understood.Objective: We aimed to identify the amino acids that modulate the circadian clock and reset the light-induced circadian phase in mice and humans.Methods: Male CBA/N mice were orally administered 1 of 20 l-amino acids, and the circadian and light-induced phase shifts of wheel-running activity were analyzed. Antagonists of several neurotransmitter pathways were injected before l-serine administration, and light-induced phase shifts were analyzed. In addition, the effect of l-serine on the light-induced phase advance was investigated in healthy male students (mean ± SD age 22.2 ± 1.8 y) by using dim-light melatonin onset (DLMO) determined by saliva samples as an index of the circadian phase.Results: l-Serine administration enhanced light-induced phase shifts in mice (1.86-fold; P < 0.05). Both l-serine and its metabolite d-serine, a coagonist of N-methyl-d-aspartic acid (NMDA) receptors, exerted this effect, but d-serine concentrations in the hypothalamus did not increase after l-serine administration. The effect of l-serine was blocked by picrotoxin, an antagonist of γ-aminobutyric acid A receptors, but not by MK801, an antagonist of NMDA receptors. l-Serine administration altered the long-term expression patterns of clock genes in the suprachiasmatic nuclei. After advancing the light-dark cycle by 6 h, l-serine administration slightly accelerated re-entrainment to the shifted cycle. In humans, l-serine ingestion before bedtime induced significantly larger phase advances of DLMO after bright-light exposure during the morning (means ± SEMs-l-serine: 25.9 ± 6.6 min; placebo: 12.1 ± 7.0 min; P < 0.05).Conclusion: These results suggest that l-serine enhances light-induced phase resetting in mice and humans, and it may be useful for treating circadian disturbances.

D-serine, a novel uremic toxin, induces senescence in human renal tubular cells via GCN2 activation

The prevalence of chronic kidney disease (CKD), characterized by progressive renal dysfunction with tubulointerstitial fibrosis, is increasing because of societal aging. Uremic toxins, accumulated during renal dysfunction, cause kidney damage, leading to renal deterioration. A recent metabolomic analysis revealed that plasma D-serine accumulation is associated with faster progression of renal dysfunction in CKD patients. However, the causal relationship and the underlying mechanisms remain unclear. Herein, we demonstrated that D-serine markedly induced cellular senescence and apoptosis in a human proximal tubular cell line, HK-2, and primary culture of human renal tubular cells. The former was accompanied by G2/M cell cycle arrest and senescence-associated secretory phenotype, including pro-fibrotic and pro-inflammatory factors, contributing to tubulointerstitial fibrosis. Integrated stress response mediated by the general control nonderepressible 2 played an important role in D-serine-induced tubular cell toxicity and pro-fibrotic phenotypes, accelerating CKD progression and kidney aging. D-serine upregulated the L-serine synthesis pathway. Furthermore, D-serine-induced suppression of tubular cell proliferation was ameliorated by L-serine administration, indicating that D-serine exposure induced an L-serine-deprived state in tubular cells, compensated by L-serine synthesis. Thus, this study unveils molecular mechanisms underlying D-serine-induced tubular damage and pro-fibrotic phenotypes, suggesting that D-serine is a uremic toxin involved in CKD pathogenesis.

Pseudomonas aeruginosa serA Gene Is Required for Bacterial Translocation through Caco-2 Cell Monolayers.

To specify critical factors responsible for Pseudomonas aeruginosa penetration through the Caco-2 cell epithelial barrier, we analyzed transposon insertion mutants that demonstrated a dramatic reduction in penetration activity relative to P. aeruginosa PAO1 strain. From these strains, mutations could be grouped into five classes, specifically flagellin-associated genes, pili-associated genes, heat-shock protein genes, genes related to the glycolytic pathway, and biosynthesis-related genes. Of these mutants, we here focused on the serA mutant, as the association between this gene and penetration activity is yet unknown. Inactivation of the serA gene caused significant repression of bacterial penetration through Caco-2 cell monolayers with decreased swimming and swarming motilities, bacterial adherence, and fly mortality rate, as well as repression of ExoS secretion; however, twitching motility was not affected. Furthermore, L-serine, which is known to inhibit the D-3-phosphoglycerate dehydrogenase activity of the SerA protein, caused significant reductions in penetration through Caco-2 cell monolayers, swarming and swimming motilities, bacterial adherence to Caco-2 cells, and virulence in flies in the wild-type P. aeruginosa PAO1 strain. Together, these results suggest that serA is associated with bacterial motility and adherence, which are mediated by flagella that play a key role in the penetration of P. aeruginosa through Caco-2 cell monolayers. Oral administration of L-serine to compromised hosts might have the potential to interfere with bacterial translocation and prevent septicemia caused by P. aeruginosa through inhibition of serA function.

Antidepressant-like effect of bright light is potentiated by L-serine administration in a mouse model of seasonal affective disorder.

Bright light therapy is used as the primary treatment for seasonal affective disorder; however, the mechanisms underlying its antidepressant effect are not fully understood. Previously, we found that C57BL/6J mice exhibit increased depression-like behavior during a short-day condition (SD) and have lowered brain serotonin (5-HT) content. This study analyzed the effect of bright light on depression-like behaviors and the brain serotonergic system using the C57BL/6J mice. In the mice maintained under SD, bright light treatment (1000 lx, daily 1 h exposure) for 1 week reduced immobility time in the forced swimming test and increased intake of saccharin solution in a saccharin intake test. However, the light treatment did not modify 5-HT content and selective 5-HT uptake in the amygdala, or temporal patterns of core body temperature and wheel-running activity throughout a day. In the next experiment, we attempted to enhance the effect of bright light by using L-serine, a precursor of D-serine that acts as an N-methyl-D-aspartic acid receptor coagonist. Daily subcutaneous injection of L-serine for 2 weeks prior to the bright light strongly reduced the immobility time in the forced swimming test, suggesting a synergistic effect of light and L-serine. Furthermore, bright light increased the total number of 5-HT-immunoreactive cells and cells that had colocalized 5-HT and c-Fos immunosignals in several subregions of the raphe nuclei. These effects were potentiated by prior injection of L-serine. These data suggest that the bright light may elicit an antidepressant-like effect via enhanced 5-HT signals in the brain and L-serine can enhance these effects.

Abstract WP133: L-serine Treatment Confers Neuroprotection Against Permanent Focal Cerebral Ischemia In Rats Via Improving Regional Cerebral Blood Flow

Introduction: L-serine plays critical roles in neuronal development and function. We have recently reported that L-serine protected against ischemic neuronal injury in vivo and in vitro. The mechanism underlying the neuroprotective effect of L-serine remains unclear. L-serine has been documented to induce a fall in mean arterial pressure through activation of small- and intermediate-conductance calcium-activated potassium channels on the endothelium. Such vasodilating action of L-serine in cerebral blood vessels has not been investigated. Hypothesis: Improving regional cerebral blood flow (rCBF) by L-serine contributes to its neuroprotection on the brain after permanent middle cerebral artery occlusion (pMCAO). Methods: Adult male Sprague-Dawley rats were randomly assigned to sham, vehicle or L-serine-treated groups. pMCAO was induced while monitoring rCBF. The neurological deficit scores, brain infarct volumes and physiological parameters were assessed. L-serine and D-serine content in the cortex was measured with high performance liquid chromatography. Results: Compared to vehicle treatment, administration of L-serine improved rCBF in the ischemic cortex and reduced the neurological deficits, infarct volume and cortical neuronal loss in a dose- and time-dependent manner. The improvement of rCBF and neuroprotective effect of L-serine were abolished by apamin plus charybdotoxin, which blocks the calcium-activated potassium channels on the endothelium, but not influenced by strychnine, an antagonist of glycine receptors. HPLC results shows that L-serine treatment increased the content of both L-serine and D-serine in the ischemic cortex. However, inhibiting the conversion of L-serine to D-serine by aminooxyacetic acid did not affect the L-serine-afforded protection, suggesting that the neuroprotective efficacy of L-serine is not related to the conversion of L-serine to D-serine. Conclusions: L-serine displayed a neuroprotective effect in the ischemic brain, at least partly due to an elevation in rCBF through cerebral blood vessel dilation mediated by the calcium-activated potassium channels on the endothelial cells. L-serine may be a potential novel therapy for ischemic brain injury.

Oral Administration of L-Serine Increases L- and D-Serine Levels in the Plasma and Brain of Fasted Rats

Oral Administration of L-Serine Increases L- and D-Serine Levels in the Plasma and Brain of Fasted Rats

Role of satellite cell-derived l-serine in the dorsal root ganglion in paclitaxel-induced painful peripheral neuropathy

Paclitaxel is one of the most commonly used anti-neoplastic drugs for the treatment of solid tumors. Unfortunately, its use is often associated with dose-limiting painful peripheral neuropathy and subsequent neuropathic pain that is resistant to standard analgesics. However, there are few clinically available drugs or drug classes for the treatment of paclitaxel-induced neuropathy due to a lack of information regarding the mechanisms responsible for it. In this study, we examined the involvement of l-serine in paclitaxel-induced hyperalgesia/allodynia and decrease in sensory nerve conduction velocity (SNCV). We used a preclinical rat model of paclitaxel-induced painful peripheral neuropathy. Response to von Frey filaments, SNCV, 3-phosphoglycerate dehydrogenase (3PGDH) expression, and l-serine concentration were examined. Effects of l-serine administration were also investigated. Paclitaxel treatment induced mechanical allodynia/hyperalgesia and reduction of SNCV. Paclitaxel also decreased the l-serine concentration in the dorsal root ganglion (DRG) but not in the sciatic nerve or spinal cord. In addition, paclitaxel decreased expression of 3PGDH, a biosynthetic enzyme of l-serine, in the DRG. Immunohistochemistry showed that 3PGDH was localized in satellite cells but not in neurons in the DRG. Intraperitoneal administration of l-serine improved both paclitaxel-induced mechanical allodynia/hyperalgesia and the reduction of SNCV. These results suggest that satellite cell-derived l-serine in the DRG plays an important role in paclitaxel-induced painful peripheral neuropathy. These findings may lead to novel strategies for the treatment of paclitaxel-induced painful peripheral neuropathy.

Decreases in splanchnic vascular resistance contribute to hypotensive effects ofl-serine in hypertensive rats

l-Serine administration reduces mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats rendered hypertensive by chronic oral treatment with the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME). To determine if the fall in MAP was due to decreases in vascular resistance or cardiac output (CO), and to record regional hemodynamic effects, we measured the distribution of fluorescent microspheres to single bolus intravenous injections of l-serine (1 mmol/kg) in 14-wk-old male WKY, SHR, and l-NAME-treated WKY rats. MAP and total peripheral resistance (TPR) were significantly higher (P < 0.01), whereas CO was lower in l-NAME-treated WKY (P < 0.01) and SHR (P < 0.05). l-Serine administration led to a rapid fall in MAP (WKY 22%, l-NAME-WKY 46%, SHR 34%,) and TPR (WKY 24%, l-NAME-WKY 68%, SHR 53%), whereas CO was elevated. In WKY rats, l-serine induced an increase in blood flow only in the small intestine (53%) while it was more profound in several vascular beds of hypertensive rats [l-NAME-WKY: small intestine (238%), spleen (184%), diaphragm (85%), and liver (65%); SHR: small intestine (217%), spleen (202%), diaphragm (116%), large intestine (105%), pancreas (96%), and liver (93%)]. Pretreatment with a combination of apamin (a small calcium-activated potassium channel inhibitor) and charybdotoxin (an intermediate calcium-activated potassium channel inhibitor) abolished the l-serine-induced changes in blood flow and TPR. l-Serine acts predominantly on apamin- and charybdotoxin-sensitive potassium channels in the splanchnic circulation to increase blood flow, thereby contributing to the fall in TPR and the pronounced blood pressure-lowering effect of l-serine in hypertensive rats.

Oral administration of l-serine reduces the locomotor activity of socially isolated rats

l-Serine is considered a functional amino acid in the central nervous system, since intracerebroventricular injection of l-serine induced sedative and hypnotic effects in neonatal chicks exposed to acute stressful conditions. Accordingly, l-serine is a candidate anti-stress factor, but the effect of daily intake of l-serine on behavior of animals exposed to chronic stress has not been investigated. In the present study, we exposed rats to social isolation stress for 4 weeks, and home cage test and open field test were concluded to evaluate the effect of l-serine on behavior. To investigate l-serine supplementation modifies the brain l-serine and its metabolite contents, free amino acid contents were measured by a high performance liquid chromatography. l-Serine in the drinking water increased l-serine levels in some brain areas, but changes in its metabolites were almost negligible. l-Serine decreased locomotor activity in rats exposed to a familiar environment. In addition, l-serine decreased exploratory behavior of isolated rats, even in a novel environment. Our results could suggest that daily intake of l-serine can attenuate symptoms induced by chronic stress.

Alterations in Plasma Levels of Amino Acids after Intracerebroventricular Administration of L-Serine or D-Serine in Conscious and Freely Moving Rats

L-Serine has a role in cellular proliferation, being a precursor for protein synthesis, and is also important for brain development. D-Serine plays a role as the endogenous co-agonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptors in the brain. Accumulating evidence suggests that abnormality of D-serine levels might be involved in the pathophysiology of schizophrenia. Using the automated blood sampling system, we examined whether or not intrac- erebroventricular (icv) infusion of L- and D-isomers of serine could affect plasma levels of amino acids in conscious and freely moving rats. The icv infusion of L-serine significantly decreased the plasma levels of glycine, glutamate, and D- serine, but not glutamine and L-serine. Furthermore, the icv infusion of D-serine significantly decreased the plasma levels of glycine, glutamate, and L-serine, but not glutamine. Expectedly, a marked increase of plasma D-serine was detected af- ter icv infusion of D-serine. These findings suggest that the metabolic pathway for L- and D-serine may be markedly dif- ferent in the rat brain. L-Serine has been shown to play a role in cellular prolif- eration, as it is a precursor for nucleotide synthesis (15-17). In addition, after the first reports of serine deficiency disor- ders (3-phosphoglycerate dehydrogenase (3-PGDH) defi- ciency and 3-phosphoserine phosphatase (3-PSP) defi- ciency)), it also became clear that L-serine and L-serine- derived metabolites are important for brain development and function (17-25). In contrast, D-serine, an isomer of L- serine, plays a role as a key co-agonist for NMDA receptors (26-32). D-Serine is produced by serine racemase (SRR) from L-serine, and D-serine has been shown to be metabo- lized by D-amino acid oxidase (DAAO) in the brain. Several