Adolescent stress increases depression-like behaviors and alters the excitatory-inhibitory balance in aged mice / 中华医学杂志(英文版)

Background@#Depression affects approximately 5% of elderly people and its etiology might be related to chronic stress exposure during neurodevelopmental periods. In this study, we examined the effects of adolescent chronic social stress in aged mice on depressive behaviors and the excitatory-inhibitory (E/I) balance in stress-sensitive regions of the brain.@*Methods@#Sixty-four adolescent, male C57BL/6 mice were randomly assigned to either the 7-week (from post-natal days 29 to 77) social instability stress (stress group, n = 32) or normal housing conditions (control group, n = 32). At 15 months of age, 16 mice were randomly selected from each group for a series of behavioral tests, including two depression-related tasks (the sucrose preference test and the tail suspension test). Three days following the last behavioral test, eight mice were randomly selected from each group for immunohistochemical analyses to measure the cell density of parvalbumin (PV+)- and calretinin (CR+)-positive gamma-aminobutyric-acid (GABA)ergic inhibitory inter-neurons, and the expression levels of vesicular transporters of glutamate-1 (VGluT1) and vesicular GABA transporter (VGAT) in three stress-sensitive regions of the brain (the medial pre-frontal cortex [mPFC], hippocampus, and amygdala).@*Results@#Behaviorally, compared with the control group, adolescent chronic stress increased depression-like behaviors as shown in decreased sucrose preference (54.96 ± 1.97% vs. 43.11 ± 2.85%, t(22) = 3.417, P = 0.003) and reduced latency to immobility in the tail suspension test (92.77 ± 25.08 s vs. 33.14 ± 5.95 s, t(25) = 2.394, P = 0.025), but did not affect anxiety-like behaviors and pre-pulse inhibition. At the neurobiologic level, adolescent stress down-regulated PV+, not CR+, inter-neuron density in the mPFC (F(1, 39) = 19.30, P < 0.001), and hippocampus (F(1, 42) = 5.823, P = 0.020) and altered the CR+, not PV+, inter-neuron density in the amygdala (F(1, 28) = 23.16, P < 0.001). The VGluT1/VGAT ratio was decreased in all three regions (all F > 10.09, all P < 0.004), which suggests stress-induced hypoexcitability in these regions.@*Conclusions@#Chronic stress during adolescence increased depression-like behaviors in aged mice, which may be associated with the E/I imbalance in stress-sensitive brain regions.

Thymosin Alpha-1 Inhibits Complete Freund's Adjuvant-Induced Pain and Production of Microglia-Mediated Pro-inflammatory Cytokines in Spinal Cord / 神经科学通报·英文版

Activation of inflammatory responses regulates the transmission of pain pathways through an integrated network in the peripheral and central nervous systems. The immunopotentiator thymosin alpha-1 (Tα1) has recently been reported to have anti-inflammatory and neuroprotective functions in rodents. However, how Tα1 affects inflammatory pain remains unclear. In the present study, intraperitoneal injection of Tα1 attenuated complete Freund's adjuvant (CFA)-induced pain hypersensitivity, and decreased the up-regulation of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in inflamed skin and the spinal cord. We found that CFA-induced peripheral inflammation evoked strong microglial activation, but the effect was reversed by Tα1. Notably, Tα1 reversed the CFA-induced up-regulation of vesicular glutamate transporter (VGLUT) and down-regulated the vesicular γ-aminobutyric acid transporter (VGAT) in the spinal cord. Taken together, these results suggest that Tα1 plays a therapeutic role in inflammatory pain and in the modulation of microglia-induced pro-inflammatory cytokine production in addition to mediation of VGLUT and VGAT expression in the spinal cord.

Vesicular Glutamate Transporter 1 (VGLUT1)- and VGLUT2-containing Terminals on the Rat Jaw-closing γ-Motoneurons

Currently, compared to jaw-closing (JC) α-motoneurons, the information on the distribution and morphology of glutamatergic synapses on the jaw-closing (JC) γ-motoneurons, which may help elucidate the mechanism of isometric contraction of the JC muscle, is very limited. This study investigated the distribution and ultrastructural features of vesicular glutamate transporter 1 (VGLUT1)- and VGLUT2-immunopositive (+) axon terminals (boutons) on JC γ-motoneurons by retrograde tracing with horseradish peroxidase, electron microscopic immunocytochemistry, and quantitative analysis. About 35% of the boutons on identified JC γ-motoneurons were VGLUT+, and of those, 99% were VGLUT2+. The fraction of VGLUT1+ boutons of all boutons and the percentage of membrane of JC γ-motoneurons covered by these boutons were significantly lower than those for the JC α-motoneurons, revealed in our previous work. The bouton volume, mitochondrial volume, and active zone area of the VGLUT2+ boutons on the JC γ-motoneurons were uniformly small. These findings suggest that the JC γ-motoneurons, in contrast to the JC α-motoneurons, receive generally weak glutamatergic synaptic input almost exclusively from VGLUT2+ premotoneurons that form direct synapse with motoneurons.

Correlation of polymorphism of glial high-affinity glutamate transporter (SLC1A3) gene and non-suicidal self-injury in adolescents / 中华行为医学与脑科学杂志

Objective To explore the correlation between polymorphisms (SNPs) of locus rs2269272 of glial high-affinity glutamate transporter (SLC1A3) gene and suicide attempt among Chinese adolescents.Methods iMLDRTM genotyping technology was used to detect the polymorphism of rs2269272 SLC1A3 gene loci in 55 suicide attempters and 112 healthy controls,and survival analysis was applied to analyze the relationship between allele (T) and the age of suicide attempt.Results The differences of rs2269272 locus allele distribution between two groups were statistically significant(x2=4.208,P=0.040),but genotype distribution of two groups had no significantly differences(x2 =4.011,P=0.135).Non-suicidal self-injury adolescents with locus rs2269272 (15.6 ± 0.4) were younger than adolescents without locus rs2269272(16.4±0.7),but the difference was not statistically significant.Conclusion Preliminary findings suggest that rs2269272 SLC1 A3 may be relevant to non-suicidal self-injury acts,and rs2269272 locus allele is not related to earlier suicide attempt.

Electroacupuncture Alleviates Motor Symptoms and Up-Regulates Vesicular Glutamatergic Transporter 1 Expression in the Subthalamic Nucleus in a Unilateral 6-Hydroxydopamine-Lesioned Hemi-Parkinsonian Rat Model / 神经科学通报·英文版

Previous studies have shown that electroacupuncture (EA) promotes recovery of motor function in Parkinson's disease (PD). However the mechanisms are not completely understood. Clinically, the subthalamic nucleus (STN) is a critical target for deep brain stimulation treatment of PD, and vesicular glutamate transporter 1 (VGluT1) plays an important role in the modulation of glutamate in the STN derived from the cortex. In this study, a 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD was treated with 100 Hz EA for 4 weeks. Immunohistochemical analysis of tyrosine hydroxylase (TH) showed that EA treatment had no effect on TH expression in the ipsilateral striatum or substantia nigra pars compacta, though it alleviated several of the parkinsonian motor symptoms. Compared with the hemi-parkinsonian rats without EA treatment, the 100 Hz EA treatment significantly decreased apomorphine-induced rotation and increased the latency in the Rotarod test. Notably, the EA treatment reversed the 6-OHDA-induced down-regulation of VGluT1 in the STN. The results demonstrated that EA alleviated motor symptoms and up-regulated VGluT1 in the ipsilateral STN of hemi-parkinsonian rats, suggesting that up-regulation of VGluT1 in the STN may be related to the effects of EA on parkinsonian motor symptoms via restoration of function in the cortico-STN pathway.

Neurochemical and behavioral characterization of neuronal glutamate transporter EAAT3 heterozygous mice

BACKGROUND: Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric condition affecting 1-3% of the worldwide population. OCD has a strong genetic component, and the SLC1A1 gene that encodes neuronal glutamate transporter EAAT3 is a strong candidate for this disorder. To evaluate the impact of reduced EAAT3 expression in vivo, we studied male EAAT3 heterozygous and wild-type littermate mice using a battery of behavioral paradigms relevant to anxiety (open field test, elevated plus maze) and compulsivity (marble burying), as well as locomotor activity induced by amphetamine. Using high-performance liquid chromatography, we also determined tissue neurotransmitter levels in cortex, striatum and thalamus-brain areas that are relevant to OCD. RESULTS: Compared to wild-type littermates, EAAT3 heterozygous male mice have unaltered baseline anxiety-like, compulsive-like behavior and locomotor activity. Administration of acute amphetamine (5 mg/kg intraperitoneally) increased locomotion with no differences across genotypes. Tissue levels of glutamate, GABA, dopamine and serotonin did not vary between EAAT3 heterozygous and wild-type mice. CONCLUSIONS: Our results indicate that reduced EAAT3 expression does not impact neurotransmitter content in the corticostriatal circuit nor alter anxiety or compulsive-like behaviors.

Anticonvulsant effect of ceftriaxone sodium in temporal lobe epilepsy / 基础医学与临床

Objective To study the effects of ceftriaxone sodium(Cef) on the seizures and the expression of glutamate transporter (GLT-1) in kainic acid (KA) epilepsy model.Methods Firstly, a chronic spontaneous seizure mouse model was established by unilateral hippocampal injection of KA and monitored by vEEG technique to record seizures.The experimental group received intraperitoneal injection of Cef 200 mg/(kg·d) and the control group received normal saline.Seizure frequency, interictal spike waves and histological phenotypes were recorded to evaluate the function of Cef.Then we use the Western blot to detect the effect of expression for GLT-1.Results Unilateral hippocampal injection of KA 200 ng successfully established the mesial temporal lobe epilepsy model.Cef can reduce the seizures from 2.145 times/day to 1.597 times/day, decreased by 31.2% with a statistical significance(P<0.05).Cef treatment did not significantly enhance the expression of GLT-1.Conclusions Intraperitoneal injection of Cef partially inhibites the seizures of KA model, but the expression of GLT-1 in hippocampus is not enhanced.It is suggested that ceftriaxone may inhibit seizures through other mechanisms.

Vesicle glutamate transporters and Alzheimer’s disease / 国际药学研究杂志

Vesicle glutamate transporter (VGLUT) specifically transfers glutamate into synaptic vesicle, determines the amount of glutamate released into the synaptic cleft, then regulates the efficiency of glutamatergic synaptic transmission. VGLUT plays an important role in the pathogenesis of Alzheimer's diseases (AD). VGLUT is significantly decreased in the brain of AD patients and closely correlated with cognitive dysfunction, beta- amyloid aggregation, tau protein phosphorylation and glutamate excitoxicity. VGLUT, the possible specific biomarker of glutamatergic neuron, has been considered a potential drug target in the treatment of AD and biomarkers in the early diagnosis of AD. There are some advances on chemicals targeting on VGLUT.

Expression of GABA and glutamate vesicular transporter in depressed mice / 重庆医学

Objective To study the expression of vesicular GABA transporter and vesicular glutamate transporter 1 in de‐pression .Methods Mice was divided into control group and defeat group stochastically .By social defeat model and social avoidance , the defeat group was divided into two groups:susceptible group and unsusceptible group .Synaptic proteins were extracted respec‐tively from the 3 groups .We detected the expression abundance of VGAT and VGLUT1 by Western blot .Results Compared with the control group ,in susceptible group ,the residence time in the contact area was significantly reduced ,and the residence time in the corner area was significantly increased ,with statistical difference(P0 .05) .In the striatum ,although the expression levels of VGAT and VGLUT1 were increased in susceptible group ,but in unsusceptible group ,the expression of these proteins also increased significantly .Conclusion The prefrontal cortex and hippo‐campus excitability and inhibitory vesicle transport were changed in depression ,which may relate to the transcription disorder .

The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia

Ampicillin, a beta-lactam antibiotic, dose-dependently protects neurons against ischemic brain injury. The present study was performed to investigate the neuroprotective mechanism of ampicillin in a mouse model of transient global forebrain ischemia. Male C57BL/6 mice were anesthetized with halothane and subjected to bilateral common carotid artery occlusion for 40 min. Before transient forebrain ischemia, ampicillin (200 mg/kg, intraperitoneally [i.p.]) or penicillin G (6,000 U/kg or 20,000 U/kg, i.p.) was administered daily for 5 days. The pretreatment with ampicillin but not with penicillin G signifi cantly attenuated neuronal damage in the hippocampal CA1 subfield. Mechanistically, the increased activity of matrix metalloproteinases (MMPs) following forebrain ischemia was also attenuated by ampicillin treatment. In addition, the ampicillin treatment reversed increased immunoreactivities to glial fibrillary acidic protein and isolectin B4, markers of astrocytes and microglia, respectively. Furthermore, the ampicillin treatment significantly increased the level of glutamate transporter-1, and dihydrokainic acid (DHK, 10 mg/kg, i.p.), an inhibitor of glutamate transporter-1 (GLT-1), reversed the neuroprotective effect of ampicillin. Taken together, these data indicate that ampicillin provides neuroprotection against ischemia-reperfusion brain injury, possibly through inducing the GLT-1 protein and inhibiting the activity of MMP in the mouse hippocampus.

Roles of glutamate transporter EAAT2 in occurrence and treatment of depression / 中国药理学通报

The glutamate transporter EAAT 2 ( rodent nomencla-ture GLT-1:glutamate transporter 1), which is a predominantly astroglial glutamate transporter in the hippocampus and the pre-frontal cortex , is responsible for the majority of extracellular glu-tamate uptake .The glutamate transporter EAAT 2 can decrease the high levels of glutamate in the synaptic cleft , avoiding gluta-matergic excitotoxicity to damage the glial cells and neurons . Currently, the transporter EAAT2 has become a research hotspot of depression .This article aims to summarize roles of glutamate transporter EAAT2 in the occurrence and treatment of depres-sion.

Effect of subarachnoid nerve block anesthesia on glutamate transporter GLAST and GLT-1 expressions in rabbits

Objective: To observe the effect of subarachnoid nerve block anesthesia on glutamate transporter glutamate-aspartate transporter (GLAST) and GLT-1 expressions in rabbits, and to investigate the effect of peripheral nerve anesthesia on the morphology and function of the spinal cord. Methods: Twenty healthy New Zealand white rabbits were randomly divided into two groups: the experimental group and control group; with 10 rabbits in each group. For spinal nerve anesthesia, 5 g/L of bupivacaine was used in the experimental group, and sterile saline was used in the control group. After 30 min of cardiac perfusion, GLAST and GLT-1 protein expression in spinal neurons were detected by immunohistochemistry and immunofluorescence staining. Results: GLAST and GLT-1 protein-positive cells increased in neurons in the experimental group, compared with the control group (P < 0.05). Conclusions: After subarachnoid nerve block anesthesia, rabbit glutamate transporter GLAST and GLT-1 expression is increased; and spinal cord nerve cell function is inhibited.

Effects of ceftriaxone on depressive-like behavior and changes of hippocampal glutamate transporter-1 in depression model C57 mice / 中华行为医学与脑科学杂志

Objective To investigate the effects of ceftriaxone on depressive-like behavior and changes of hippocampal glutamate transporter-1 (GLT-1) in C57 mice depression model,and to further explore the molecular mechanism of ceftriaxone on antidepressant action.Methods Thirty male C57 mice were randomly divided into control group(group A,n=10),CUS group(group B,n=10) and CUS+ceftriaxone group(group C,n=10).The mice of the CUS group and the CUS+ceftriaxone group were subjected to chronic unpredictable stress (CUS) for 2 sessions per day for 21 days.Then,the mice of the CUS+ceftriaxone group were given ceftriaxone for 21 days.Behavioral changes were assessed by the sucrose preference test and open field test.The GLT-1 protein levels in the hippocampus were detected by Western blot analysis at the end of the ceftriaxone treatment.Results (1) Compared with the control group,the percentage of sucrose preference,the total traveled distance,the moved velocity,and the frequencies of rearing of the CUS group were significantly decreased(P＜0.05) at the 21 days.However,the percentage of sucrose preference ((78.74 ± 3.54) ％),the total traveled distance ((6818.35 ± 505.14) cm),the moved velocity((12.36±0.89) cm/s),and the frequencies of rearing(58.20±4.05) of the CUS+ceftriaxone group at the end of the ceftriaxone treatment were improved significantly compared with the CUS group ((59.46 ± 2.75) ％,(2931.71±271.89) cm,(5.84±0.42) cm/s,(26.20±2.62),P＜0.05).(2) Western blot analysis indicated significant reductions of the GLT-1 protein levels in the hippocampus of CUS group (versus the control mice:P ＜0.05),and chronic ceftriaxone treatment reversed the CUS-induced decrease in the GLT-1 levels(P＜0.05).Conclusion Ceftriaxone might significantly improve depressive-like behavior in C57 mice depression model.Chronic unpredictable stress (CUS) could down-regulate the GLT-1 protein levels in the hippocampus,which are reversed by ceftriaxone.These results further support the notion enhanced expression of the GLT-1 protcin can be molecular mechanism of ceftriaxone on antidepressant action.

Effects of fluoxetine on changes of GLT-1 in rat prefrontal cortex after chronic unpredictable stress / 中国药理学通报

Aim To investigate the effects of fluoxe-tine on the changes of of protein levels of GLT-1 in pre-frontal cortex in rat depression model, and to further explore the molecular mechanism of antidepressant ac-tion of fluoxetine. Methods Sixty male SD rats were randomly assigned into three groups: control group, chronic unpredictable stress ( CUS) group, and CUS+fluoxetine group. The rats of CUS group and CUS+flu-oxetine group were subjected to CUS for 2 sessions per day for 35 days. Then, the rats of the CUS+fluoxetine group were given fluoxetine for 28 days. Behavioral changes were assessed by the sucrose preference and open field tests. The GLT-1 protein levels in the pre-frontal cortex were detected by immunohistochemistry and Western blot analysis at the end of the fluoxetine treatment. Results ( 1 ) Compared with the control group,sucrose preference, total traveling distance, ve-locity and frequencies of rearing were reduced in the CUS group ( P < 0. 01 ) . These behavioral changes could be reversed after 28 day fluoxetine treatment. (2 ) Immunohistochemistry assay indicated weak im-munoreactivity for GLT-1 in the prefrontal cortex of CUS group ( versus the control rats: P <0. 01 ); the immunoreactivity for GLT-1 of the fluoxetine-treated rats was significantly up-regulated compared with the CUS group rats ( P<0. 01 ) . ( 3 ) Western blot analy-sis indicated significant reductions of GLT-1 in the pre-frontal cortex of CUS group ( versus the control rats:P<0. 01 ) , and chronic fluoxetine treatment reversed the CUS-induced decrease in GLT-1 levels ( P <0. 01 ) . Conclusions Chronic unpredictable stress ( CUS ) could down-regulate the GLT-1 protein levels in the prefrontal cortex, which is reversed by fluoxe-tine. These results further support the notion that en-hanced expression of the GLT-1 protein could be mo-lecular mechanism of fluoxetine antidepressant effect.

Effect of subarachnoid nerve block anesthesia on glutamate transporter GLAST and GLT-1 expressions in rabbits

OBJECTIVE@#To observe the effect of subarachnoid nerve block anesthesia on glutamate transporter glutamate-aspartate transporter (GLAST) and GLT-1 expressions in rabbits, and to investigate the effect of peripheral nerve anesthesia on the morphology and function of the spinal cord.@*METHODS@#Twenty healthy New Zealand white rabbits were randomly divided into two groups: the experimental group and control group; with 10 rabbits in each group. For spinal nerve anesthesia, 5 g/L of bupivacaine was used in the experimental group, and sterile saline was used in the control group. After 30 min of cardiac perfusion, GLAST and GLT-1 protein expression in spinal neurons were detected by immunohistochemistry and immunofluorescence staining.@*RESULTS@#GLAST and GLT-1 protein-positive cells increased in neurons in the experimental group, compared with the control group (P < 0.05).@*CONCLUSIONS@#After subarachnoid nerve block anesthesia, rabbit glutamate transporter GLAST and GLT-1 expression is increased; and spinal cord nerve cell function is inhibited.

Evaluation of Ampicillin and Ceftriaxone on Ethanol Consumption as Compared to Naltrexone in Alcohol Dependant Rats.

Context: Extracellular glutamate level in reward centre of brain increases during ethanol drinking sessions. Hence, it can be hypothesized that drugs which decrease extracellular glutamate might have deaddictive properties. It has been shown that β-lactam antibiotics are potent stimulators of glutamate transporter 1(GLT1) expression. Previous studies have shown that ceftriaxone decreases ethanol consumption but this has not been compared to standard line of treatment (naltrexone). Also, no study was conducted for testing ampicillin even if in an in-vitro experiment ampicillin has shown to increase GLT1 levels more than ceftriaxone. Hence, our study’s objectives were to compare efficacy of ceftriaxone and ampicillin with naltrexone on ethanol consumption in rats. Methods: Permission of ethics committee was taken. Study was divided into two parts. Part I included standardization of model & Part II included 8 groups of six rats each. Group 1: vehicle control, Group 2: 1mg/kg/d naltrexone, Group 3: 100mg/kg/d ceftriaxone, Group 4: 200mg/kg/d ceftriaxone, Group 5: 100mg/kg/d ampicillin, Group 6: 200mg/kg/d ampicillin were given i.p injections for 15 days and Group 7: 200mg/kg ceftriaxone & Group 8: 200mg/kg ampicillin i.p. single dose. Parameters measured were ethanol & water intake per day for 15 days. Results: Groups 2 to 8 showed statistically significant decrease in ethanol intake as compared to vehicle control. Also, group 3 & 4 showed an increase in water consumption as compared to Group 1. Conclusions: Our study recommends that drugs acting on glutamate pathways like ceftriaxone and ampicillin can be explored for treatment of alcohol dependence.

A preliminary evaluation of comparative effectiveness of riluzole in therapeutic regimen for irritable bowel syndrome

Objective: To develop agents that are specifically effective in controlling the key disturbance of visceral hyperalgesia besides abating of associated multiple symptoms, and evaluate comparative effectiveness for IBS symptom relief for standard regimen (antispasmodic and probiotic) and add-on amitriptyine or riluzole regimens following two weeks administration.Methods:groups were studied. First group received standard treatment (mebeverine 200 mg twice daily and probiotic 200 mg twice daily). Second group received add-on amitriptyline 25 mg before bedtime, while the third group got add-on riluzole 50 mg twice daily. Overall gastrointestinal symptom rating scale improving symptoms and hospital anxiety depression scale improving associated psychological morbidity were employed as measures at induction and at two-week follow-up period. Individual symptom scores were also examined to define the outcome profiles.Results:108 patients with visceral hypersensitivity accompanying IBS, divided into three rating scale score, not the other two regimens. Pain relief was seen with both riluzole and amitriptyline regimens significantly superior to standard treatment regimen, but riluzole effect appeared specific and independent anxiolytic effect. Amitriptyline caused relief in diarrhea and did not benefit in constipation point to non-specific remedial role in IBS. Riluzole regimen resulted in significant reduction of overall gastrointestinal symptom Conclusions: Riluzole specifically relieves visceral hypersensitivity and is proved to be superior to current treatments in IBS patients. It appears a lead remedy based on glutamate transporter mechanisms in visceral hypersensititvity.

Inhibitors of vesicular glutamate transporter: Research advances / 国际药学研究杂志

Vesicular glutamate transporter (VGLUT), located on the vesicular membrane, is a highly specific marker of glut- amatergic neurons. VGLUT selectively transports glutamate in the cytoplasm into vesicles. VGLUT1, VGLUT2 and VGLUT3 are three subtypes of VGLUT. The VGLUT can influence the glutamatergic synaptic transmission through mediating sequestration, storage and release of glutamate. The number and activity of VGLUT can change the level of glutamate in synapse cleft through mediating sequestration, storage and release of glutamate, then influence the glutamatergic synaptic transmission. To improve this pathological situation and maintain glutamate at the physiologically relevant concentration, VGLUT inhibition is required. Several classes of competitive VGLUT inhibitors have emerged including azo dyes, substituted quinolines, fatty acids and alkaloids. This article provides a brief review on the structure and function of these potential VGLUT inhibitors.

A preliminary evaluation of comparative effectiveness of riluzole in therapeutic regimen for irritable bowel syndrome

<p><b>OBJECTIVE</b>To develop agents that are specifically effective in controlling the key disturbance of visceral hyperalgesia besides abating of associated multiple symptoms, and evaluate comparative effectiveness for IBS symptom relief for standard regimen (antispasmodic and probiotic) and add-on amitriptyine or riluzole regimens following two weeks administration.</p><p><b>METHODS</b>108 patients with visceral hypersensitivity accompanying IBS, divided into three groups were studied. First group received standard treatment (mebeverine 200 mg twice daily and probiotic 200 mg twice daily). Second group received add-on amitriptyline 25 mg before bedtime, while the third group got add-on riluzole 50 mg twice daily. Overall gastrointestinal symptom rating scale improving symptoms and hospital anxiety depression scale improving associated psychological morbidity were employed as measures at induction and at two-week follow-up period. Individual symptom scores were also examined to define the outcome profiles.</p><p><b>RESULTS</b>Riluzole regimen resulted in significant reduction of overall gastrointestinal symptom rating scale score, not the other two regimens. Pain relief was seen with both riluzole and amitriptyline regimens significantly superior to standard treatment regimen, but riluzole effect appeared specific and independent anxiolytic effect. Amitriptyline caused relief in diarrhea and did not benefit in constipation point to non-specific remedial role in IBS.</p><p><b>CONCLUSIONS</b>Riluzole specifically relieves visceral hypersensitivity and is proved to be superior to current treatments in IBS patients. It appears a lead remedy based on glutamate transporter mechanisms in visceral hypersensititvity.</p>

Inhibitors of vesicular glutamate transporter:research advances / 国际药学研究杂志

Vesicular glutamate transporter(VGLUT), located on the vesicular membrane, is a highly specific marker of glut-amatergic neurons. VGLUT selectively transports glutamate in the cytoplasm into vesicles. VGLUT1, VGLUT2 and VGLUT3 are three subtypes of VGLUT. The VGLUT can influence the glutamatergic synaptic transmission through mediating sequestration, storage and release of glutamate. The number and activity of VGLUT can change the level of glutamate in synapse cleft through mediating sequestration,storage and release of glutamate,then influence the glutamatergic synaptic transmission. To improve this pathological situation and maintain glutamate at the physiologically relevant concentration, VGLUT inhibition is required. Several classes of competitive VGLUT inhibitors have emerged including azo dyes, substituted quinolines, fatty acids and alkaloids. This article provides a brief review on the structure and function of these potential VGLUT inhibitors.