Polymorphisms of Ionotropic Glutamate Receptor-Related Genes and the Risk of Autism Spectrum Disorder in a Chinese Population

OBJECTIVE: To evaluate the association of GRIK2 and NLGN1 with autism spectrum disorder in a Chinese population. METHODS: We performed spatio-temporal expression analysis of GRIK2 and NLGN1 in the developing prefrontal cortex, and examined the expression of the genes in ASD cases and healthy controls using the GSE38322 data set. Following, we performed a case-control study in a Chinese population. RESULTS: The analysis using the publicly available expression data showed that GRIK2 and NLGN1 may have a role in the development of human brain and contribute to the risk of ASD. Later genetic analysis in the Chinese population showed that the GRIK2 rs6922753 for the T allele, TC genotype and dominant model played a significant protective role in ASD susceptibility (respectively: OR=0.840, p=0.023; OR=0.802, p=0.038; OR=0.791, p=0.020). The NLGN1 rs9855544 for the G allele and GG genotype played a significant protective role in ASD susceptibility (respectively: OR=0.844, p=0.019; OR=0.717, p=0.022). After adjusting p values, the statistical significance was lost (p>0.05). CONCLUSION: Our results suggested that GRIK2 rs6922753 and NLGN1 rs9855544 might not confer susceptibility to ASD in the Chinese population.

Regulatory Effects of Ionotropic and GroupⅠ Metabotropic Glutamate Receptors on Temperature Hypersensitivity in Rats / 中国医科大学学报

Objective To study the effects of ionic and group Ⅰ metabotropic glutamate receptors on rats' thermal hypersensitivity by intraplantar administration of drugs. Methods After intraplantar administration of glutamate receptor agonists,L-glutamic acid (Glu), N-methyl-D-aspartic-acid (NMDA),and (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide (AMPA);a Group Ⅰ mGluR agonist, (S) 3,5-dihydroxyphenylglycine [(S)-DHPG];a noncompetitive NMDA receptor antagonist, (+)-MK801 maleate (MK-801);a competitive AMPA/kainate receptor antagonist,6-cyano-7-nitroquinoxaline-2,3-dione (CNQX);and a selective GroupⅠ mGluR antagonist,7-hydroxyiminocyclo propan[b]chromen-1a- carboxylic acid ethyl ester (cpccoEt) into the left hind paws of rats whose L5-6 nerves were sham-operated or ligated,we examined the response of the rats to thermal stimuli provided by radiant heat. Results In sham-operated rats,glutamate,NMDA,AMPA,and (S)-DHPG reduced paw withdrawal latency (PWL) but did not have any effect on SNL rats. However,in SNL rats,MK-801,CNQX,and cpccoEt increased PWL but exerted no effect on sham-operated rats. Conclusion These results suggest that changes in sensitivity of peripheral ionic and group Ⅰ metabotropic glutamate receptors can lead to changes in peripheral nerve plasticity;the generation and maintenance of neuropathic pain caused by nerve injury is based on this plasticity.

Metabotropic glutamate receptor 5 may be involved in macrophage plasticity

Abstract Background Macrophages are a functionally heterogeneous cell population and depending on microenvironments they polarize in two main groups: M1 and M2. Glutamic acid and glutamate receptors may participate in the regulation of macrophage plasticity. To investigate the role of glutamatergic systems in macrophages physiology, we performed the transfection of mGluR5 cDNAs into RAW-264.7 cells. Results Comparative analysis of modified (RAW-mGluR5 macrophages) and non-modified macrophages (RAW-macrophages) has shown that the RAW-mGluR5 macrophages absorbed more glutamate than control cells and the amount of intracellular glutamate correlated with the expression of excitatory amino acid transporters -2 (EAAT-2). Besides, our results have shown that RAW-mGluR5 macrophages expressed a higher level of peroxisome proliferator-activated receptor γ (PPAR-γ) and secreted more IL-10, high mobility group box 1 proteins (HMGB1) and Galectin-3 than control RAW-macrophages. Conclusions We propose that elevation of intracellular glutamate and expression of mGluR5 may initiate the metabolic rearrangement in macrophages that could contribute to the formation of an immunosuppressive phenotype.

Glutamate Agonists May Affect the Hematological Profile in Healthy Rats.

Aims: Even though glutamate is one of the primary endogenous amino acids of the Central Nervous System (CNS) its subunit receptors exist also in non-neuronal tissues outside CNS such as the hematopoietic system. The purpose of this paper is to define the possible in vivo effect of glutamate ionotropic agonist Monosodium l-glutamate (MSG) in the hematopoietic system of Wistar adult rats. Methodology: MSG was administrated intravenously in male Wistar rats of 250-350g weight. Animals treated with MSG (n = 24) were compared to a control group (n = 10). Full blood count with differential, aggregation intensity and bone marrow cellularity were evaluated 12 and 24 hours after drug administration. The results were analyzed by unpaired t-test. Results: MSG showed to affect white blood cell count in a negative way whereas it provoked an increase in Hemoglobin (Hb) and Hematocrit (Hct) levels. Aggregation was only transiently affected using ADP as an agonist and bone marrow counts showed a trend towards normalization. Conclusion: It is concluded that MSG can affect the hematological profile and bone marrow cellular composition of healthy intact rats as well as blood elements functions. Our results suggest a possible role for glutamate receptors on the hematopoietic system’s pathophysiology. Further research is needed in order to better characterize the in vivo effect of glutamate receptors agonists and antagonists on blood elements and bone marrow.

The expression of glutamate receptor in hippocampus of neonatal rats with hypoxic-ischemic brain damage / 临床儿科杂志

Objective To study the expression of Ca-A/K channel-related molecules glutamate receptor 2 and 1(GluR2/1) in hippocampus tissues of neonatal rats with hypoxic-ischemic brain damage (HIBD). Methods A total of 60 7-day-old Sprague-Dawley rats were randomly divided into sham operation group and HIBD group. Hippocampal tissues were obtained at 0 h, 1 h, 6 h, 24 h, 48 h and 72 h after HIBD. The expression of GluR2, GluR1 and autophagy marker protein Beclin-1, LC3 were detected by Western blot assay. Results Edema and focal softening and necrosis were observed 6 h after HIBD in the brains of neonatal rats. Compared with Con group, at each time point, the expression levels of GluR2 were lower while the levels of GluR1, Beclin-1 and LC3 were higher significantly in HIBD group (P<0.05). The protein levels of LC3, Beclin-1, GluR1 and GluR2 in hippocampus tissues of HIBD group were significantly different among different time points after the estab-lishment of HIBD model (F=10.65~701.14, P<0.01). The protein level of GluR2 was decreased from 1 h to 24 h after HIBD and reached the lowest level at 24 h. The levels of GluR1, Beclin-1 and LC3 were increased at 6 h, plateaued at 24 h and remained there until 48 h. The levels of these proteins returned back to the initial level at 72 h. Conclusions Ca-A/K channel-related mol-ecules GluR2 and GluR1 play important roles in the autophagic cell death of hippocampus tissues in neonatal rats with hypoxic-ischemic brain damage.

Regulation of metabotropic glutamate subtype 7 and 8 receptors in nucleus tractus solitarius in cardiac nociception in rats / 吉林大学学报(医学版)

Objective To explore the role of metabotropic glutamate receptors (mGluRs)group Ⅲ and its subtypes mGluR7 and mGluR8 in nucleus tractus solitarius(NTS)in cardiac-somatic motor reflex (CMR),and to clarify the modulation role of mGluR Ⅲ and its subtypes in NTS in cardiac nociceptoion.Methods 40 SD rats were randomly divided into L-AP4 group,microinjection of mGluRs Ⅲ agonist L-AP4 0.1,1.0,10.0 or 20.0 nmol in NTS;AMN082 group,microinjection of mGluR7 agonist AMN082 1,2 or 4 nmol;DCPG group,microinjection of mGluR8 agonist DCPG 4, 6 or 8 nmol;MSOP group, microinjection of mGluR Ⅲ antagonist MSOP 20 or 100 nmol,20 nmol MSOP+410 nmol L-AP,20 nmol MSOP+2 nmol AMN082,20 nmol MSOP+6 nmol DCPG. The changes of CMR of the rats in various groups were observed.Results Compared with control,the CMR in L-AP4 and AMN082 groups was decreased (P0.05);the CMR in MSOP group after injection of 100 nmol MSOP was increased (P0.05).Conclusion The group Ⅲ mGluRs in the NTS play an inhibitory role in cardiac nociception, and mGluR7 has anti-nociceptive effects while mGluR8 has pro-nociceptive effects.

Changes of the amino acid receptors in solitary tract nucleus of rats with spinal cord injury / 第二军医大学学报

Objective: To investigate the changes of the amino acid receptors in solitary tract nucleus(NTS)of rats after spinal cord injury (SCI). Methods: The rat model of T4 spinal cord transection was used in this study. The study was divided into SCI group(n=5)and Control group(n=5). Changes in mean arterial pressure (MAP) and heart rate (HR) were observed at 1,2,3,4, and 6 weeks after SCI; and the protein expression of the glutamate N-methyl-D-aspartate receptor 1 (NMDA-R1) and gamma-aminobutyric acid receptor A α1 (GABAA-α1) in the NTS were detected by Western blotting analysis at different time points. Results: The MAP level was significantly decreased at 1-3 weeks after SCI (P<0.05), and it gradually recovered 4 weeks after SCI; the HR was significantly increased 1-4 weeks after SCI (P<0.05) and recovered at the 6th week. The results of Western blotting analysis showed that the protein expression of GABAA-α1 was significantly increased 2 weeks after SCI and significantly reduced at 4 and 6 weeks after SCI (P<0.05). Moreover, the ratio of NMDA-R1 to GABAA-α1 expression in NTS was significantly elevated after SCI(P<0.05). Conclusion: The adaptable changes of important receptors in the NTS following SCI may improve SCI-induced cardiovascular dysfunction.

Modelling and drug designing of glutamate receptor involved in alzheimer’s disease.

Glutamate receptors dysfunction plays an important role in the pathogenesis and disturbance which is probably a secondary phenomenon to other neurochemical, genetic or metabolic changes, and essential to the development of Alzheimer Disease. Glutamate receptors are synaptic receptors, which are located on the membranes of neuronal cells. Glutamate is used to assemble proteins and also it is abundant in many areas of the body, but it also functions as a neurotransmitter and is particularly abundant in the nervous system. In this work we have modeled a three dimensional structure for Glutamate [NMDA] receptor subunit using MODELLER7V7 software with 2RC7 (Crystal Structure of the NR3A Ligand Binding Core Complex with Glycine) as template. With the aid of Molecular dynamics and Molecular simulations studies it was identified that the generated structure was reliable. This structure was used to identify better inhibitor using docking studies. The drug derivatives were docked to the Glutamate receptor structure into the active site containing residues such as ASP21, LEU30, TYR31, HIS59, and MET60. Among the 21 derivatives 14 were docked and 3rd drug derivative showed better docking energy than the others. Our experimental studies can be further used to develop a better drug for Alzheimer disease.

Malnutrition affects the pressor response to microinjection of L-glutamate into the RVLM of awake rats

Post-weaning protein malnutrition is often related to the development of cardiovascular and metabolic diseases in humans, as well to changed content of neurotransmitters in the central nervous system under experimental conditions. The rostral ventrolateral medulla (RVLM) is a bulbar region that contains sympathetic premotor neurons; the excitatory amino acid L-glutamate seems to be the main neurotransmitter at this level. The aim of the present study was to evaluate the possible change in the L-glutamate sensitivity of the RVLM neurons of malnourished animals. Male Fischer rats were divided into two groups: control (n = 15) and malnourished (n = 19). Four days before the experiments, guide cannulas were implanted bilaterally in direction of the RVLM for microinjection of L-glutamate. Twenty-four hours before the experiments, the femoral artery was cannulated for cardiovascular recordings. The results showed that the baseline heart rate increased in malnourished compared to control animals (412.18 ± 16.03 bpm vs. 370.74 ± 9.59 bpm, respectively). Malnourished animals presented a dissimilar concentration-dependent pressor response curve to L-glutamate and an attenuated baroreflex gain. Our results suggest that post-weaning protein restriction affects glutamatergic neurotransmission of the baroreflex at the RVLM level.

Intrathecal administration of metabotropic glutamate receptor subtype 5 antagonist on pain behavior and spinal astrocytes activation in mouse mod of bone cancer pain / 中华行为医学与脑科学杂志

Objective To investigate effects of metabotropic glutamate receptor subtype 5 (mGluR5) antagonist MTEP on the nociceptive behavior and the expression of glial fibrillary acidic protein (GFAP) in spinal cord associated with bone cancer pain. Methods C3H/HeNCrlVr 60 male mice were randomly divided into 5 groups: ( 1 ) normal control group: the mice were given food and water ad libitum; ( 2 ) MTEP + Tumor group: the mice were treated by intrathecal gdministration ( once daily on the days 14 ～20 after inoculation of tumor cells)with MTEP (150 nmol); (3) physiological saline + Tumor group:the tumor mice were treated with the same volume of physiological saline; (4) MTEP + Sham group: the sham mice were treated with the same dose of MTEP;(5) physiological saline + Sham group: the sham mice were treated with the same volume of physiological saline.the mice pain behaviors were assessed with the paw withdrawal thermal latency (PWTL) at the corresponding time points, then the mice were killed and the samples of spinal cord were used to real-time PCR and western blot detection of GFAP mRNA and protein expression. Results The basic values of PWTL had no significant differences among all groups (P＜0.05). At day 14 after operation,no significant difference was found in the PWTL value between normal control group and the sham operation group. But in tumor group, the PWTL value was significantly lower than in the normal control group (P＜ 0.05 ). At day 21 after operation,the PWTL and the level of GFAP expression in the spinal cord had no significant differences among normal control group, MTEP + Sham group and physiological saline + Sham group (P ＞ 0.05 ); the PWTL ( (6. 18 ± 1.29 ) s) in physiological saline + Tumor group was significantly lower than in normal control group ( ( 15.91 ± 1.65 )s), physiological saline + Sham group ( ( 16.57 ± 1.86) s) and MTEP + Sham group ( ( 17.05 ± 2.43 ) s) (P ＜ 0.05 ), but the level of GFAP expression was higher than in the above three groups. In MTEP +Tumor group ,the PWTL (9.39 ± 1.94s) was higher than in physiological saline + Tumor group, and the level of GFAP expression was lower than in physiological saline +Tumor group (P ＜ 0.05 ). Conclusion Inhibiting spinal activation of astrocytes may be one of the MTEP anticancer pain mechanisms.

Ácido domoico e intoxicación amnésica por moluscos en salud pública: [revisión] / Domoic acid and amnesic shellfish poisoning in public health: [review]

El ácido domoico es una biotoxina marina que por primera vez produjo una intoxicación alimentaria en más de cienpersonas en 1987 en Canadá, con muerte en algunos de ellos después de la ingesta de mejillones contaminados. Dentro de las manifestaciones clínicas destacó la amnesia anterógrada, no vista con ninguna biotoxina ni fármaco conocido, pudiendo llegar a ser permanente, por lo cual el síndrome fue denominado intoxicación amnésica por moluscos. En el examen histopatológico del cerebro de los fallecidos, se encontró que el hipocampo fue una de las estructuras más afectadas, con necrosis celular en algunas áreas, lo que explicó el deterioro irreversible de la memoria. Se ha encontrado que muchas especies de mariscos, peces filtradores, krill y animales marinos, pueden contaminarse con dicha biotoxinaque es producida por algunas algas microscópicas y que muchas veces son responsables de las denominadas mareas rojas. La biotoxina puede llegar al humano por la cadena alimenticia. En este artículo, se revisa los brotes tóxicos en mamíferos y aves marinas con posterior muerte debido al ácido domoico, el mecanismo en la producción de toxicidad, su agonismo en los receptores glutamatérgicos, la importancia en la salud pública, sus riesgos por evaluar en la salud humana, así como la difusión de la biotoxina por el mundo, incluyendo el Océano Pacífico y las posibles razones de tal difusión, así como su importancia ecológica y económica que ha obligado a la vigilancia mundial.

Domoic acid is a sea biotoxin that was first identified to produce food poisoning in more than a hundred people inCanada, in 1987, with some deaths reported, after intake of contaminated mussels. As part of the clinical presentation, anterograde amnesia is highlighted. As it had not been seen before with any know biotoxin or drug, and could be permanent, the syndrome was called amnesic poisoning due to shellfish. In the histopathological examination of the brain of the dead patients, the hippocampus was one of the most affected, showing cellular necrosis in some areas, which explains the irreversible deterioration of the memory. Many shellfish species, filtrating fish, krill and marine animalscan get contaminated by the biotoxin , which is produced by microscopic algae, which are often responsible of the redtides. The biotoxin can reach the human being through the food chain. In this article, we revise the toxic outbreaks inmammals and marine birds, causing death due to domoic acid, the mechanism of toxicity production, its agonism in the glutamatergic receptors, its importance in public health, the risk they pose to human health and ought to be evaluated, and the diffusion of the biotoxin throughout the world, including the Pacific Ocean and the possible reasons of this diffusion, as well as its ecologic and economic importance, which has made it surveillance compulsory in all the world.

Quantitative Autoradiographic Study on Receptor Regulation in the Basal Ganglia in Rat Model of Levodopa-induced Motor Complications / 华中科技大学学报（医学）（英德文版）

In order to study neurotransmitter receptor regulation in the basal ganglia involved in the functional changes underlying levodopa-induced motor complications,quantitative autoradiography was used to observe receptor bindings of dopamine D1 and D2,N-methyl-D-aspartate (NMDA),amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) and amino butyric acid (GABA) in the basal ganglia of rats that had unilateral nigrostriatal lesions and had been chronically treated with levodopa until motor complications developed.The rats were randomly assigned to three groups:normal,denervated and treatment-complicated groups.The results showed that response duration to levodopa became progressively shorter and abnormal involuntary movement (AIM) score was progressively increased during the course of levodopa treatment.Chronic treatment augmented DI receptors more than denervation,and reduced D2 receptors that were also increased by dopamine denervation.Striatal NMDA receptors were substantially up-regulated in the treatment-complicated group.Levodopa treatment did not change receptors of nigral AMPA,pailidai GABA,and subthalamic GABA,which remained the same as that in denervation group.However,chronic treatment reversed the increase ofnigral GABA receptors caused by the lesion.It was concluded that a shortening of response duration and AIM mimicked levodopa-induced motor complications of Parkinson's patients.These data suggested that up-regulation of dopamine D1 and NMDA receptors in the striatum leads to an imbalance of stimulation through the striatal output pathways,which is associated with levodopa-induced motor complications.

Spinal Metabotropic Glutamate Receptors (mGluRs) are Involved in the Melittin-induced Nociception in Rats

Intraplantar injection of melittin has been known to induce sustained decrease of mechanical threshold and increase of spontaneous flinchings. The present study was undertaken to investigate how the melittin-induced nociceptive responses were modulated by changes of metabotropic glutamate receptor (mGluR) activity. Changes in paw withdrawal threshold (PWT), number of flinchings and paw thickness were measured at a given time point after injection of melittin (10microgram/paw) into the mid-plantar area of rat hindpaw. To observe the effects of mGluRs on the melittin-induced nociceptions, group I mGluR (AIDA, 100microgram and 200microgram), mGluR1 (LY367385, 50microgram and 100microgram) and mGluR5 (MPEP, 200microgram and 300microgram) antagonists, group II (APDC, 100microgram and 200microgram) and III (L-SOP, 100microgram and 200microgram) agonists were intrathecally administered 20 min before melittin injection. Intraplantar injection of melittin induced a sustained decrease of mechanical threshold, spontaneous flinchings and edema. The effects of melittin to reduce mechanical threshold and to induce spontaneous flinchings were significantly suppressed following intrathecal pre-administration of group I mGluR, mGluR1 and mGluR5 antagonists, group II and III mGluR agonists. Group I mGluR antagonists and group II and III mGluR agonists had no significant effect on melittin-induced edema. These experimental findings indicate that multiple spinal mGluRs are involved in the modulation of melittin-induced nociceptive responses.

The Role of Central Group I mGluRs for CFA-induced Knee Joint Pain Model in Rats / 대한마취과학회지

BACKGROUND: Glutamate is the predominant excitatory neurotransmitter in the central and peripheral nervous system and has known to be involved in nociceptive transmission and central sensitization. It acts through ligand gated ionotropic glutamate receptors (iGluRs) and G protein-coupled metabotropic glutamate receptors (mGluRs). And mGlu 1, 5 receptors have been recognized to play a role in nociceptive processing. We want to investigate whether central mGluR1 and mGluR5 antagonists could reverse the behavioral signs of weight bearing and secondary mechanical hyperalgesia induced by chronic knee joint inflammation. METHODS: MGluR1 antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA: 25, 50, 100 microM/10 microliter, n = 7 per group) and selective mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP: 25, 100, 200 nM/10 microliter, n = 7 per group) were injected intrathecally 5 days after Complete Freund's Adjuvant (CFA, 150 microliter) injection into knee joint and behavior signs of weight bearing and secondary mechanical hyperalgesia were observed. RESULTS: CFA significantly reduced the magnitude of right hind paw weight bearing and decreased the withdrawal threshold to mechanical stimulation compared to contralateral side. Higher dose of AIDA (100 microM) significantly reversed the reduction of weight bearing, but MPEP did not. AIDA reversed the decrease of the paw withdrawal threshold to mechanical stimulation at the dosage of 50 and 100 microM respectively. MPEP significantly increased the paw withdrawal threshold to mechanical stimulation in a dose dependent manner. CONCLUSIONS: Group I mGluRs were involved in maintenance of primary and secondary mechanical hyperalgesia.

Antinociceptive Effects of Intrathecal Metabotropic Glutamate Receptor Compounds and Morphine in Rats / 대한통증학회지

BACKGROUND: Spinal metabotropic glutamate receptors (mGluRs) and opioid receptors are involved in the modulation of nociception. Although opioid receptors agonists are active for pain, the effects of the compounds for the mGluRs have not been definitely investigated at the spinal level. We examined the effects of the intrathecal mGluR compounds and morphine in the nociceptive test, and then we further clarified the role of the spinal mGluRs. In addition, the nature of the pharmacological interaction after the coadministration of mGluRs compounds with morphine was determined. METHODS: Catheters were inserted into the intrathecal space of male SD rats. For the induction of pain, 50microl of 5% formalin solution or a thermal stimulus was applied to the hindpaw. An isobolographic analysis was used for the evaluation of the drug interaction. RESULTS: Neither group I mGluR compounds nor group III mGluR compounds produced any antinociceptive effect in the formalin test. The group II mGluR agonist (APDC) had little effect on the formalin-induced nociception. The group II mGluR antagonist (LY 341495) caused a dose-dependent suppression of the phase 2 flinching response on the formalin test, but it did not reduce the phase 1 response of the formalin test nor did it increase the withdrawal latency of the thermal stimulus. Isobolographic analysis revealed a synergistic interaction after the intrathecal delivery of a LY 341495-morphine mixture. CONCLUSIONS: These results suggest that group II mGluRs are involved in the facilitated processing at the spinal level, and the combination of LY 341495 with morphine may be useful to manage the facilitated pain state.

The protective effect of LY367385 on impairment of cultured mouse cerebral cortical neurons induced by sodium glutamate or oxygen-glucose deprivation / 中国康复理论与实践

@#ObjectiveTo investigate the protective effect of LY367385 on impairment of cultured mouse cerebral cortical neurons induced by sodium glutamate (Glu) or oxygen-glucose deprivation (OGD).MethodsNeuron damage induced by Glu or OGD, as well as the action of (S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) were measured by determining the leakage of lactate dehydrogenase (LDH) from neurons. Immunocytochemistry and immunofluorescent methods were used to detect the expression of anti-mGluR1α. Morphological observation of primary cortical neurons was performed by phase contrast microscope.ResultsFollowing the exposure to 0.1 mmol/L Glu for 1 h or OGD for 1 h, LDH leakage from neurons obviously increased (P< 0.01 ). 50 mmol/L LY367385, when co-incubated with Glu or OGD, markedly reduced the LDH leakage (P<0.01). The 24-h leakage of LDH was increased from cells exposed to 0.1 mmol/L Glu for 15 min. Pre-and post-treatment with LY367385 (50 mmol/L ) decreased the leakage of LDH. The cultured neurons expressed mGluR1α.ConclusionLY367385 has protective effect on neurons damaged by Glu or OGD. It may be related to antagonizing mGluR1α.

Group Ⅱ and Ⅲ metabotropic glutamate receptors agonists reverse 1-methyl-4-phenylpyridinium-induced glutamate uptake inhibition in C6 glioma cells / 中国临床药理学与治疗学

AIM: To study the effect of group Ⅱ and Ⅲ metabotropic glutamate receptors (mGluRs) agonists on 1-methyl-4-phenylpyridinium (MPP~+)-induced glutamate uptake inhibition in C6 glioma cells. METHODS: The glutamate uptake into astrocytes was measured by using radio-ligand binding assay method. RESULTS: It was shown that Group Ⅱ mGluRs agonist (2' S, 2' R, 3 ' R) -2- (2', 3 ' -dicarboxycyclopropyl) glycine (DCG-Ⅳ) (100 ?mol?L~(-1)) and Group Ⅲ mGluRs agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) (100 ?mol?L~(-1)) significantly reversed MPP~+-induced glutamate uptake inhibition. Furthermore, the enhancement effects of DCG-Ⅳ and L-AP4 were blocked by their respective antagonists, (RS)-1 -Amino-5-phosphonoinan-1-carboxylic acid (APICA) and (RS)-?-methylserine-O-phosphate (MSOP). CONCLUSION: Group Ⅱ and Ⅲ mGluRs agonists produce neuroprotective effects by enhancing the activity of glutamate transporters.

Neurotransmitter receptor regulation after deafferentation in the visual system

The present study aimed at understanding the regulation of AMPA-type glutamate receptors (GluRs) and nicotinic acetylcholine receptors (nAChRs) during experimentally-induced neurodegeneration in the chick visual system. Immunohistochemistry, in situ hybridization, and RNAse protection techniques were used to verify the expression of GluR and nAChR subunits at several periods after deafferentation, ranging from 1 to 30 days. The results indicate that GluR1 and 2 expression changes in a biphasic way after deafferentation, decreasing after the shortest survival periods (1-4 days) and increasing afterwards. These effects clearly involve regulation of gene expression, as verified by in situ hybridization and RNAse protection. The regulation of the α2, α4, α5, and β2 nAChR subunits after deafferentation, on the other hand, exhibited a pattern that was exactly the opposite, with an early increase followed by a consistent decrease of expression until 30 days postlesion. Furthermore, nAChR changes were not apparently due to gene expression regulation, but instead by up-regulation/ down-regulation at a protein level. These results suggest that neurotransmitter receptors undergo differential plastic changes after deafferentation in the nervous system and contribute data to their possible role in neurodegeneration and neuroprotection processes.

Modulation of Amygdala Synaptic Transmission by Metabotropic Glutamate Receptors

Metabotropic glutamate receptors (mGluRs), classified into three groups (group I, II, III), play a critical role in modulation of synaptic transmission at central and peripheral synapses. In the present study, extracellular field potential recording techniques were used to investigate effects of mGluR agonists on excitatory synaptic transmission at thalamic input synapses onto the lateral amygdala. The non-selective mGluR agonist t-ACPD (100 microM) produced reversible, short-term depression, but the group III mGluR agonist L-AP4 (50 microM) did not have any significant effects on amygdala synaptic transmission, suggesting that group I and/or II mGluRs are involved in the modulation by t-ACPD. The group I mGluR agonist DHPG (100 microM) produced reversible inhibition as did t-ACPD. Unexpectedly, the group II mGluR agonist LCCG-1 (10 microM) induced long-term as well as short-term depression. Thus, our data suggest that activation of group I or II mGluRs produces short-term, reversible depression of excitatory synaptic transmission at thalamic input synapses onto the lateral amygdala. Considering the long-term effect upon activation of group II mGluRs, lack of long-term effects upon activation of group I and II mGluRs may indicate a possible cross-talk among different groups of mGluRs.

Metabotropic glutamate receptors and related nervous diseases / 中国药理学通报

Excessive release of glutamic acid plays an important role in the occurring and development of many nervous system diseases.Ionotropic glutamate receptors antagonists are shown to have therapeutic effect in animal models,but their clinical application is limited by their effects of blocking the normal excitatory neurotransmission.However,metabotropic glutamate receptors can suppress the release of glutamic via presynaptic mechanisms,which makes them the new targeting points of certain nervous system disease.This paper reviews the recent research progress of mGluRs in nervous diseases both at home and abroad.