Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug resistance.Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy.Meta...Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug resistance.Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy.Metabotropic glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic plasticity.Dysregulated mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of epilepsy.In this review,we first introduce the three groups of mGluRs and their associated signaling pathways.Then,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in epileptogenesis.In addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also summarized.We hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.展开更多
Autophagy has been suggested to participate in the pathology of hypoxic-ischemic brain damage(HIBD).However,its regulatory role in HIBD remains unclear and was thus examined here using a rat model.To induce HIBD,the...Autophagy has been suggested to participate in the pathology of hypoxic-ischemic brain damage(HIBD).However,its regulatory role in HIBD remains unclear and was thus examined here using a rat model.To induce HIBD,the left common carotid artery was ligated in neonatal rats,and the rats were subjected to hypoxia for 2 hours.Some of these rats were intraperitoneally pretreated with the autophagy inhibitor 3-methyladenine(10 m M in 10 μL) or the autophagy stimulator rapamycin(1 g/kg) 1 hour before artery ligation.Our findings demonstrated that hypoxia-ischemia-induced hippocampal injury in neonatal rats was accompanied by increased expression levels of the autophagy-related proteins light chain 3 and Beclin-1 as well as of the AMPA receptor subunit GluR 1,but by reduced expression of GluR 2.Pretreatment with the autophagy inhibitor 3-methyladenine blocked hypoxia-ischemia-induced hippocampal injury,whereas pretreatment with the autophagy stimulator rapamycin significantly augmented hippocampal injury.Additionally,3-methyladenine pretreatment blocked the hypoxia-ischemia-induced upregulation of Glu R1 and downregulation of GluR2 in the hippocampus.By contrast,rapamycin further elevated hippocampal Glu R1 levels and exacerbated decreased GluR2 expression levels in neonates with HIBD.Our results indicate that autophagy inhibition favors the prevention of HIBD in neonatal rats,at least in part,through normalizing Glu R1 and GluR2 expression.展开更多
BACKGROUND:Studies have reported that potassium channel openers exhibit a protective effect on cerebral ischemia-reperfusion injury and inhibit glutamate excitotoxicity in rats.However,the effects of the glutamate re...BACKGROUND:Studies have reported that potassium channel openers exhibit a protective effect on cerebral ischemia-reperfusion injury and inhibit glutamate excitotoxicity in rats.However,the effects of the glutamate receptor 1α and glutamate transporter 1 remain poorly understood.OBJECTIVE:To investigate the prophylactic use of the adenosine triphosphate-sensitive potassium channel opener cromakalim on neurological function and cerebral infarct size,as well as glutamate receptor 1α and glutamate transporter 1 expression,in rats with cerebral ischemia-reperfusion injury,and to explore action mechanisms underlying reduced glutamate excitotoxicity and neuroprotection in rats.DESIGN,TIME AND SETTING:Randomized,controlled,animal experiment was performed at the Brain Institute,Qingdao University Medical College,Between July 2008 and April 2009.MATERIALS:Cromakalim was purchased from Sigma,USA; rabbit anti-glutamate receptor 1α polyclonal antibody was offered by Wuhan Boster,China; rabbit anti-glutamate transporter 1 polyclonal antibody was offered by Santa Cruz Biotechnology,USA.METHODS:Sixty male,Wistar rats,aged 6 months,were randomly assigned to three groups (n =20):sham-surgery,model,and cromakalim.Intraluminal thread methods were used to establish middle cerebral artery occlusion in rats from the model and cromakalim groups.Rats from the sham-surgery group were subjected to exposed common carotid artery,external carotid artery,and internal carotid artery,without occlusion.Cromakalim (10 mg/kg) was administered 30 minutes prior to middle cerebral artery occlusion,but there was no intervention in the model and sham-surgery groups.MAIN OUTCOME MEASURES:At 24 hours post-surgery,neurological behavioral functions were evaluated using Bederson's test,cerebral infarction volume was determined following tetrazolium chloride staining,and glutamate receptor 1a and glutamate transporter 1 expressions were detected using immunohistochemistry.RESULTS:Following cerebral ischemia-reperfusion injury,neurological behavioral malfunctions were obvious in all mice.Focal cerebral infarction was detected in ischemic hemispheres,glutamate receptor 1α expression increased,and glutamate transporter 1 expression decreased in the ischemic hemisphere (P〈 0.05).Compared with the model group,neurological behavioral functions significantly improved,cerebral infarction volume was significantly reduced (P〈 0.05),glutamate receptor 1α expression was significantly decreased,and glutamate transporter 1 expression was increased in the cromakalim group (P 〈 0.05).CONCLUSION:Improved neurological function and reduced cerebral infarction volume in rats through the preventive use of cromakalim could be related to decreased glutamate receptor 1α expression and enhanced glutamate transporter 1 expression.展开更多
Metabotropic glutamate receptor 5 (mGluR5) is expressed by neurons in zones of active neurogenesis and is involved in the development of neural stem cells in vivo and in vitro. We examined the expression of mGluR5 i...Metabotropic glutamate receptor 5 (mGluR5) is expressed by neurons in zones of active neurogenesis and is involved in the development of neural stem cells in vivo and in vitro. We examined the expression of mGluR5 in the cortex and hippocampus of rats during various prenatal and postnatal periods using immunohistochemistry. During prenatal development, mGluR5 was pdmadly localized to neuronal somas in the forebrain. During early postnatal periods, the receptor was mainly present on somas in the cortex, mGluR5 immunostaining was visible in apical dendrites and in the neuropil of neurons and persisted throughout postnatal development. During this period, pyramidal neurons were strongly labeled for the receptor. In the hippocampal CA1 region, mGluR5 immunoreactivity was more intense in the stratum oriens, stratum radiatum, and lacunosum moleculare at P0, P5 and P10 relative to P60. mGluR5 expression increased significantly in the molecular layer and decreased significantly in the granule cell layer of the dentate gyrus at P5, P10 and P60 in comparison with P0. Furthermore, some mGluR5-positive cells were also bromodeoxyuridine- or NeuroD-positive in the dentate gyrus at P14. These results demonstrate that mGluR5 has a differential expression pattern in the cortex and hippocampus during early growth, suggesting a role for this receptor in the control of domain specific brain developmental events.展开更多
Traumatic brain injury causes gene expression changes in different brain regions. Occurrence and development of traumatic brain injury are closely related, involving expression of three factors, namely cyclooxygenase-...Traumatic brain injury causes gene expression changes in different brain regions. Occurrence and development of traumatic brain injury are closely related, involving expression of three factors, namely cyclooxygenase-2, glutamate receptor-2, and platelet activating factor receptor. However, little is known about the correlation of these three factors and brain neuronal injury. In this study, primary cultured rat hippocampal neurons were subjected to fluid percussion injury according to Scott’s method, with some modifications. RT-PCR and semi-quantitative immunocytochemical staining was used to measure the expression levels of cyclooxygenase-2, glutamate receptor-2, and platelet activating factor receptor. Our results found that cyclooxygenase-2 expression were firstly increased post-injury, and then decreased. Both mRNA and protein expression levels reached peaks at 8 and 12 hours post-injury, respectively. Similar sequential changes in glutamate receptor 2 were observed, with highest levels mRNA and protein expression at 8 and 12 hours post-injury respectively. On the contrary, the expressions of platelet activating factor receptor were firstly decreased post-injury, and then increased. Both mRNA and protein expression levels reached the lowest levels at 8 and 12 hours post-injury, respectively. Totally, our findings suggest that these three factors are involved in occurrence and development of hippocampal neuronal injury.展开更多
The human glutamate receptor delta 2 gene (GRID2) shares 90%homology with the orthologous mouse gene. The mouse Grid2 gene is involved with functions of the cerebellum and sponta-neous mutation of Grid2 leads to a s...The human glutamate receptor delta 2 gene (GRID2) shares 90%homology with the orthologous mouse gene. The mouse Grid2 gene is involved with functions of the cerebellum and sponta-neous mutation of Grid2 leads to a spinocerebellar ataxia-like phenotype. To investigate whether such mutations occur in humans, we screened for mutations in the coding sequence of GRID2 in 24 patients with familial or sporadic spinocerebellar ataxia and in 52 normal controls. We de-tected no point mutations or insertion/deletion mutations in the 16 exons of GRID2. However, a polymorphic 4 nucleotide deletion (IVS5-121_-118 GAGT) and two single nucleotide polymor-phisms (c.1251G〉T and IVS14-63C〉G) were identiifed. The frequency of these polymorphisms was similar between spinocerebellar ataxia patients and normal controls. These data indicate that spontaneous mutations do not occur in GRID2 and that the incidence of spinocerebellar ataxia in humans is not associated with GRID2 mutation or polymorphisms.展开更多
BACKGROUND: Developmental seizures are pathologically characterized by regenerative sprouting of hippocampal mossy fibers rich in Zn^2+. Zn^2+ metabolism in the mossy fiber pathway, and Zn^2+ accumulation in presy...BACKGROUND: Developmental seizures are pathologically characterized by regenerative sprouting of hippocampal mossy fibers rich in Zn^2+. Zn^2+ metabolism in the mossy fiber pathway, and Zn^2+ accumulation in presynaptic membrane vesicles, are dependent on zinc transporter 1 (ZnT1) and glutamate receptor subunit 2 (GluR2). OBJECTIVE: To investigate the effects of long-term recurrent neonatal seizure, in the presence and absence of physical exercise, on the developmental expression of hippocampal zinc transporter 1 (ZnT1) and GluR2, and on cognitive function in rats. DESIGN, TIME AND SETTING: Based on behavioral examination and molecular biological research, a randomized, controlled animal experiment was performed at the Department of Neurobiology, Medical College of Soochow University, between January 2007 and April 2008. MATERIALS: Twenty-one 6-day-old Sprague Dawley rats of either gender were employed in this study. ZnT1 mRNA in situ hybridization kit was provided by Tianjin Haoyang Biological Manufacture Co.,Ltd., China. Rabbit anti-GluR2 was purchased from Santa Cruz Biotech, Inc, USA. METHODS: Rats were randomly divided into a recurrent seizure group (n = 11) and a control group (n = 10). In the recurrent seizure group, 30-minute seizure was induced by flurothyl gas inhalation for a total of 6 consecutive days. Rats from the control group underwent experimental procedures similar to the recurrent seizure group, with the exception of flurothyl gas inhalation. Thirty minutes of treadmill exercise was performed daily by all rats at postnatal days 51–56. MAIN OUTCOME MEASURES: At postnatal day 82, rat hippocampal tissue was harvested for analysis of hippocampal ZnT1 and GluR2 expression by in situ hybridization and immunohistochemistry, respectively. Rat learning and memory capabilities were examined using the Y-maze test. RESULTS: In the recurrent seizure group, the gray scale value of ZnT1 in situ hybridization positive neurons in the hippocampal CA3 region was significantly greater (P 〈 0.05), while the gray scale value of GluR2 immunoreactive neurons in the hippocampal hilus and dentate gyrus was significantly lower (P 〈 0.05), than in the control group. At postnatal days 29–35, numbers of trials to criteria for successful learning were greater in the recurrent seizure group than in the control group (P 〈 0.05); at postnatal days 61–67, the numbers of trials to criteria for successful learning were similar between the two groups (P 〉 0.05). At postnatal days 29–35 and 61–67, there was no significant difference in memory capability between the recurrent seizure and control groups (P 〉 0.05). CONCLUSION: Physical exercise likely improves the learning deficits caused by recurrent neonatal seizure in rats during brain development by modulating ZnT1 and GluR2 expression.展开更多
The present study established a rat cortical neuronal model of in vitro mechanical injury. At 30 minutes after injury, the survival rate of the injured cortical neurons was decreased compared with normal neurons, and ...The present study established a rat cortical neuronal model of in vitro mechanical injury. At 30 minutes after injury, the survival rate of the injured cortical neurons was decreased compared with normal neurons, and was gradually decreased with aggravated degree of injury. Reverse transcription-polymerase chain reaction results showed that at 1 hour after injury, there was increased expression of metabotropic glutamate receptor la in cortical neurons. Immunohistochemical staining results showed that at 30 minutes after injury, the number of metabotropic glutamate receptor 1a-positive cells increased compared with normal neurons. At 12 hours after injury, lactate dehydrogenase activity in the (RS)-l-aminoindan-1, 5-dicarboxylic acid (AIDA)-treated injury neurons was si[jnificantly decreased than that in the pure injury group. At 1 hour after injury, intracellular free Ca"+ concentration was markedly decreased in the AIDA-treated injury neurons than that in the pure injury neurons. These findings suggest that after mechanical injury to cortical neurons, metabotropic glutamate receptor la expression increased. The resulting increase in intracellular free Ca2+ concentration was blocked by AIDA, indicating that AIDA exhibits neuroprotective effects after mechanical injury.展开更多
The diffuse brain injury model was conducted in Sprague-Dawley rats, according to Marmarou's free-fall attack. The water content in brain tissue, expression of metabotropic glutamate receptor la mRNA and protein were...The diffuse brain injury model was conducted in Sprague-Dawley rats, according to Marmarou's free-fall attack. The water content in brain tissue, expression of metabotropic glutamate receptor la mRNA and protein were significantly increased after injury, reached a peak at 24 hours, and then gradually decreased. After treatment with the competitive antagonist of metabotropic glutamate receptor la, (RS)-l-aminoindan-1,5-dicarboxylic acid, the water content of brain tissues decreased between 12-72 hours after injury, and neurological behaviors improved at 2 weeks. These experimental findings suggest that the 1-aminoindan-1, 5-dicarboxylic acid may result in marked neuroprotection against diffuse brain injury.展开更多
Dopaminergic neurotoxicity is characterized by damage and death of dopaminergic neurons.Parkinson's disease(PD)is a neurodegenerative disorder that primarily involves the loss of dopaminergic neurons in the substa...Dopaminergic neurotoxicity is characterized by damage and death of dopaminergic neurons.Parkinson's disease(PD)is a neurodegenerative disorder that primarily involves the loss of dopaminergic neurons in the substantia nigra.Therefore,the study of the mechanisms,as well as the search for new targets for the prevention and treatment of neurodegenerative diseases,is an important focus of modern neuroscience.PD is primarily caused by dysfunction of dopaminergic neurons;however,other neurotransmitter systems are also involved.Research reports have indicated that the glutamatergic system is involved in different pathological conditions,including dopaminergic neurotoxicity.Over the last two decades,the important functional interplay between dopaminergic and glutamatergic systems has stimulated interest in the possible role of metabotropic glutamate receptors(mGluRs)in the development of extrapyramidal disorders.However,the specific mechanisms driving these processes are presently unclear.The participation of the universal neuronal messenger nitric oxide(NO)in the mechanisms of dopaminergic neurotoxicity has attracted increased attention.The current paper aims to review the involvement of mGluRs and the contribution of NO to dopaminergic neurotoxicity.More precisely,we focused on studies conducted on the rotenone-induced PD model.This review is also an outline of our own results obtained using the method of electron paramagnetic resonance,which allows quantitation of NO radicals in brain structures.展开更多
Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system.However,it is not clear the mechanism by which mast cells communicate with peripheral nerves.We p...Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system.However,it is not clear the mechanism by which mast cells communicate with peripheral nerves.We previously found that mast cells located within healing tendons can express glutamate receptors,raising the possibility that mast cells may be sensitive to glutamate signaling.To evaluate this hypothesis,we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type(NMDAR1,NMDAR2A,and NMDAR2B)and the metabotropic type(mGluR2 and mGluR7)at both the mRNA and protein levels.The binding of glutamate to glutamate receptors on the mast cell surface was confirmed.Further,glutamate had extensive effects on gene expression in the mast cells,including the upregulation of proinflammatory components such as IL-6 and CCL2.Glutamate also induced the upregulation of transcription factors,including Egr2,Egr3 and,in particular,FosB.The extensive induction of FosB was confirmed by immunofluorescence assessment.Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate,supporting the supposition of a functional glutamate–glutamate receptor axis in mast cells.Finally,we provide in vivo evidence supporting a functional glutamate–glutamate receptor axis in the mast cells of injured tendons.Together,these findings establish glutamate as an effector of mast cell function,thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.展开更多
Neuroadaptations of glutamatergic transmission in the limbic reward circuitry are linked to persistent drug addiction.Accumulating data have demonstrated roles of ionotropic glutamate receptors and groupⅠandⅡmetabot...Neuroadaptations of glutamatergic transmission in the limbic reward circuitry are linked to persistent drug addiction.Accumulating data have demonstrated roles of ionotropic glutamate receptors and groupⅠandⅡmetabotropic glutamate receptors(mGluRs)in this event.Emerging evidence also identifies Gαi/o-coupled groupⅢmGluRs(mGluR4/7/8 subtypes enriched in the limbic system)as direct substrates of drugs of abuse and active regulators of drug action.Auto-and heteroreceptors of mGluR4/7/8 reside predominantly on nerve terminals of glutamatergic corticostriatal and GABAergic striatopallidal pathways,respectively.These presynaptic receptors regulate basal and/or phasic release of respective transmitters to maintain basal ganglia homeostasis.In response to operant administration of common addictive drugs,such as psychostimulants(cocaine and amphetamine),alcohol and opiates,limbic groupⅢmGluRs undergo drastic adaptations to contribute to the enduring remodeling of excitatory synapses and to usually suppress drug seeking behavior.As a result,a loss-of-function mutation(knockout)of individual groupⅢreceptor subtypes often promotes drug seeking.This review summarizes the data from recent studies on three groupⅢreceptor subtypes(mGluR4/7/8)expressed in the basal ganglia and analyzes their roles in the regulation of dopamine and glutamate signaling in the striatum and their participation in the addictive properties of three major classes of drugs(psychostimulants,alcohol,and opiates).展开更多
Objective Metabotropic glutamate receptor 5 (mGluR5) is concentrated in zones of active neurogenesis in the prenatal and postnatal rodent brain and plays an important role in the regulation of neurogenesis. However,...Objective Metabotropic glutamate receptor 5 (mGluR5) is concentrated in zones of active neurogenesis in the prenatal and postnatal rodent brain and plays an important role in the regulation of neurogenesis. However, little is known about mGluR5 in the prenatal human brain. Here, we aimed to explore the expression pattern and cellular distribution of mGluR5 in human fetal hippocampus. Methods Thirty-four human fetuses were divided into four groups according to gestational age: 9-11, 14-16, 22-24 and 32-36 weeks. The hippocampus was dissected out and prepared. The protein and mRNA expression of mGluR5 were evaluated by Western blot and immunohistochemistry or real-time PCR. The cellular distribution of mGluR5 was observed with double-labeling immunofluorescence. Results Both mGluR5 mRNA and protein were detected in the prenatal human hippocampus by real-time PCR and immunoblotting, and the expression levels increased gradually over time. The immunohistochemistry results were consistent with immunoblotting and showed that mGluR5 immunoreactivity was mainly present in the inner marginal zone (IMZ), hippocampal plate (HP) and ventricular zone (VZ). The double-labeling immunoftuorescence showed that mGluR5 was present in neural stem cells (nestin-positive), neuroblasts (DCX-positive) and mature neurons (NeuN-positive), but not in typical astrocytes (GFAP- positive). The cells co-expressing mGluR5 and nestin were mainly located in the IMZ, HP and subplate at 11 weeks, all layers at 16 weeks, and CA 1 at 24 weeks. As development proceeded, the number of mGluR5/nestin double-positive cells decreased gradually so that there were only a handful of double-labeled cells at 32 weeks. However, mGluR5/DCX double-positive cells were only found in the HP, IZ and IMZ at 11 weeks. Conclusion The pattern ofmGluR5 expression by neural stern/progenitor cells, neuroblasts and neurons provides important anatomical evidence for the role of mGluR5 in the regulation of human hippocampal development.展开更多
The synthetic studies for some known modulators of metabotropic glutamate receptors (mGluRs) such as (S)-αM4CPG, (1S,3R)-ACPD, L-CCG-I are described. Based on the structure of αM4CPG several new conformationally con...The synthetic studies for some known modulators of metabotropic glutamate receptors (mGluRs) such as (S)-αM4CPG, (1S,3R)-ACPD, L-CCG-I are described. Based on the structure of αM4CPG several new conformationally constrained analogues are design ed and synthesized. Among them APICA is a selective antagonist for group II mGluRs. Also, a new benzolactam-V8 analogue is found to have better isoform-selectivity for protein kine C family. Three different protocols for synthesizing benzolactam-VS analogues are developed to meet the requirement for delivering more analogues to test.展开更多
Grapes,one of the oldest tree species globally,are rich in vitamins.However,environmental conditions such as low temperature and soil salinization significantly affect grape yield and quality.The glutamate receptor(GLR...Grapes,one of the oldest tree species globally,are rich in vitamins.However,environmental conditions such as low temperature and soil salinization significantly affect grape yield and quality.The glutamate receptor(GLR)family,comprising highly conserved ligand-gated ion channels,regulates plant growth and development in response to stress.In this study,11 members of the VvGLR gene family in grapes were identified using whole-genome sequence analysis.Bioinformatic methods were employed to analyze the basic physical and chemical properties,phylogenetic trees,conserved domains,motifs,expression patterns,and evolutionary relationships.Phylogenetic and collinear analyses revealed that the VvGLRs were divided into three subgroups,showing the high conservation of the grape GLR family.These members exhibited 2 glutamate receptor binding regions(GABAb and GluR)and 3-4 transmembrane regions(M1,M2,M3,and M4).Real-time quantitative PCR analysis demonstrated the sensitivity of all VvGLRs to low temperature and salt stress.Subsequent localization studies in Nicotiana tabacum verified that VvGLR3.1 and VvGLR3.2 proteins were located on the cell membrane and cell nucleus.Additionally,yeast transformation experiments confirmed the functionality of VvGLR3.1 and VvGLR3.2 in response to low temperature and salt stress.Thesefindings highlight the significant role of the GLR family,a highly conserved group of ion channels,in enhancing grape stress resistance.This study offers new insights into the grape GLR gene family,providing fundamental knowledge for further functional analysis and breeding of stress-resistant grapevines.展开更多
BACKGROUND: Injection of glutamate (Glu) in normal animals can cause neuronal c-Fos expression; however, whether Glu can induce spinal neuronal c-Fos expression in pain models is unclear. OBJECTIVE: To examine the...BACKGROUND: Injection of glutamate (Glu) in normal animals can cause neuronal c-Fos expression; however, whether Glu can induce spinal neuronal c-Fos expression in pain models is unclear. OBJECTIVE: To examine the effects of intraplantar and intrathecal injection of Glu on c-Fos expression in the L5 spinal cord dorsal horn Ⅰ/Ⅱ and Ⅲ/Ⅳ layers after spinal nerve ligation, and to study the effects of the N-methyI-D-aspartic acid (NMDA) receptor antagonist, D-2-amino-5-phosphonopentanoate (D-AP5), and a selective group I mGluR antagonist, 7-hydroyiminocyclo propan[a]chromen-lacarboxylic acid ethyl ester (cpccoEt). DESIGN, TIME AND SETTING: A randomized, controlled animal study was performed at the Department of Pharmacology, Oral Anatomy, and Neurobiology, Osaka University Graduate School of Dentistry, from December 2005 to December 2006. MATERIALS: Glu (5 μmol), D-AP5 (50 nmot) and cpccoEt (250 nmol) were provided by Wako Pure Chemical Industries, Osaka, Japan, and diluted in saline (50 μL). The pH of all solutions was adjusted to 7.4. METHODS: Twelve rats were randomly divided into sham operation (n = 6) and spinal nerve ligation (SNL; n = 6) groups for behavioral assessments of neuropathic pain after ligation surgery of the left L5-6 nerve segment. Another 60 rats were randomly divided into sham operation, SNL, saline-intraplantar, saline-intrathecal, Glu-intraplantar, Glu-intrathecal, D-AP5-intrathecal, Glu-D-AP5-intrathecal, cpccoEt-intrathecal, and Glu-cpccoEt-intrathecal groups, with 6 rats in each group. All groups except sham operation group received a similar SNL. On day 14, rats received a 50-μL injection of saline, Glu, D-AP5, and/or cpccoEt into the left intraplantar or intrathecal L5-4 segments. MAIN OUTCOME MEASURES: The number of c-Fos positive neurons in both Ⅰ/Ⅱ and Ⅲ/Ⅳ spinal layers at L6 was observed using immunohistochemistry 2 hours after administration. RESULTS: (1) SNL increased the level of c-Fos expression in two sides of the spinal cord, particularly on Ⅲ/Ⅳ spinal layers of the ligated side. (2) Intraplantar or intrathecal administration of saline significantly increased the c-Fos labeled neurons in Ⅰ/Ⅱ spinal layers of the ligated side, compared with SNL alone (P 〈 0.01). (3) Intraplantar Glu (5 μmol) increased the number of c-Fos positive neurons in Ⅰ/Ⅱ spinal layers compared with intraplantar saline (P〈 0.01). (4) The number of c-Fos neurons in Ⅰ/Ⅱ spinal layers on both the ipsilateral and contralateral side after intraplantar Glu was lower than intrathecal Glu (P〈 0.01), with a 3-fold higher induction by intrathecal Glu. (5) Co-administration of D-AP5 or cpccoEt reduced the effects of intrathecal Glu (P 〈 0.01). CONCLUSION: Intrathecal Glu increases c-Fos expression more than intraplantar Glu. Antagonists of NMDA and group I mGluRs block this effect.展开更多
Insufficient sleep has been correlated to many physiological and psychoneurological disorders.Over the years,our understanding of the state of sleep has transcended from an inactive period of rest to a more active sta...Insufficient sleep has been correlated to many physiological and psychoneurological disorders.Over the years,our understanding of the state of sleep has transcended from an inactive period of rest to a more active state involving important cellular and molecular processes.In addition,during sleep,electrophysiological changes also occur in pathways in specific regions of the mammalian central nervous system(CNS).Activity mediated synaptic plasticity in the CNS can lead to long-term and sometimes permanent strengthening and/or weakening synaptic strength affecting neuronal network behaviour.Memory consolidation and learning that take place during sleep cycles,can be affected by changes in synaptic plasticity during sleep disturbances.G-protein coupled receptors(GPCRs),with their versatile structural and functional attributes,can regulate synaptic plasticity in CNS and hence,may be potentially affected in sleep deprived conditions.In this review,we aim to discuss important functional changes that can take place in the CNS during sleep and sleep deprivation and how changes in GPCRs can lead to potential problems with therapeutics with pharmacological interventions.展开更多
Glutamine and glutamate are major bioenergy substrates for normal and cancer cell growth.Cancer cells need more biofuel than normal tissues for energy supply,anti-oxidation activity and biomass production.Genes relate...Glutamine and glutamate are major bioenergy substrates for normal and cancer cell growth.Cancer cells need more biofuel than normal tissues for energy supply,anti-oxidation activity and biomass production.Genes related to metabolic chains in many cancers are somehow mutated,which makes cancer cells more glutamate dependent.Meanwhile,glutamate is an excitatory neurotransmitter for conducting signals through binding with different types of receptors in central neuron system.Interestingly,increasing evidences have shown involvement of glutamate signaling,guided through their receptors,in human malignancy.Dysregulation of glutamate transporters,such as excitatory amino acid transporter and cystine/glutamate antiporter system,also generates excessive extracellular glutamate,which in turn,activates glutamate receptors on cancer cells and results in malignant growth.These features make glutamate an attractive target for anti-cancer drug development with some glutamate targeted but blood brain barrier impermeable anti-psychosis drugs under consideration.We discussed the relevant progressions and drawbacks in this field herein.展开更多
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...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 D1 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, pallidal GABA, and subthalamic GABA, which remained the same as that in denervation group. However, chronic treatment reversed the increase of nigral 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.展开更多
基金supported by the Natural Science Foundation of Hunan Province,No.2021JJ30389(to JG)the Key Research and Development Program of Hunan Province of China,Nos.2022SK2042(to LL)and 2020SK2122(to ET)。
文摘Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug resistance.Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy.Metabotropic glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic plasticity.Dysregulated mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of epilepsy.In this review,we first introduce the three groups of mGluRs and their associated signaling pathways.Then,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in epileptogenesis.In addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also summarized.We hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.
基金supported by the National Natural Science Foundation of China,No.81471488,81271378,81502157,and 81501291the Key Medical Subjects of Jiangsu Province of China,No.XK201120+3 种基金the Jiangsu Province Key Research and Development of Special Funds in China,No.BE2015644the Science and Technology Project of Suzhou City of China,No.SYSD2013105,SYS201446,SYS201441the Public Health Technology Project of Suzhou City of China,No.SS201536the Department of Pediatrics Clinical Center of Suzhou City of China,No.Szzx201504
文摘Autophagy has been suggested to participate in the pathology of hypoxic-ischemic brain damage(HIBD).However,its regulatory role in HIBD remains unclear and was thus examined here using a rat model.To induce HIBD,the left common carotid artery was ligated in neonatal rats,and the rats were subjected to hypoxia for 2 hours.Some of these rats were intraperitoneally pretreated with the autophagy inhibitor 3-methyladenine(10 m M in 10 μL) or the autophagy stimulator rapamycin(1 g/kg) 1 hour before artery ligation.Our findings demonstrated that hypoxia-ischemia-induced hippocampal injury in neonatal rats was accompanied by increased expression levels of the autophagy-related proteins light chain 3 and Beclin-1 as well as of the AMPA receptor subunit GluR 1,but by reduced expression of GluR 2.Pretreatment with the autophagy inhibitor 3-methyladenine blocked hypoxia-ischemia-induced hippocampal injury,whereas pretreatment with the autophagy stimulator rapamycin significantly augmented hippocampal injury.Additionally,3-methyladenine pretreatment blocked the hypoxia-ischemia-induced upregulation of Glu R1 and downregulation of GluR2 in the hippocampus.By contrast,rapamycin further elevated hippocampal Glu R1 levels and exacerbated decreased GluR2 expression levels in neonates with HIBD.Our results indicate that autophagy inhibition favors the prevention of HIBD in neonatal rats,at least in part,through normalizing Glu R1 and GluR2 expression.
基金Shandong Provincial Science and Technology Plan Foundation
文摘BACKGROUND:Studies have reported that potassium channel openers exhibit a protective effect on cerebral ischemia-reperfusion injury and inhibit glutamate excitotoxicity in rats.However,the effects of the glutamate receptor 1α and glutamate transporter 1 remain poorly understood.OBJECTIVE:To investigate the prophylactic use of the adenosine triphosphate-sensitive potassium channel opener cromakalim on neurological function and cerebral infarct size,as well as glutamate receptor 1α and glutamate transporter 1 expression,in rats with cerebral ischemia-reperfusion injury,and to explore action mechanisms underlying reduced glutamate excitotoxicity and neuroprotection in rats.DESIGN,TIME AND SETTING:Randomized,controlled,animal experiment was performed at the Brain Institute,Qingdao University Medical College,Between July 2008 and April 2009.MATERIALS:Cromakalim was purchased from Sigma,USA; rabbit anti-glutamate receptor 1α polyclonal antibody was offered by Wuhan Boster,China; rabbit anti-glutamate transporter 1 polyclonal antibody was offered by Santa Cruz Biotechnology,USA.METHODS:Sixty male,Wistar rats,aged 6 months,were randomly assigned to three groups (n =20):sham-surgery,model,and cromakalim.Intraluminal thread methods were used to establish middle cerebral artery occlusion in rats from the model and cromakalim groups.Rats from the sham-surgery group were subjected to exposed common carotid artery,external carotid artery,and internal carotid artery,without occlusion.Cromakalim (10 mg/kg) was administered 30 minutes prior to middle cerebral artery occlusion,but there was no intervention in the model and sham-surgery groups.MAIN OUTCOME MEASURES:At 24 hours post-surgery,neurological behavioral functions were evaluated using Bederson's test,cerebral infarction volume was determined following tetrazolium chloride staining,and glutamate receptor 1a and glutamate transporter 1 expressions were detected using immunohistochemistry.RESULTS:Following cerebral ischemia-reperfusion injury,neurological behavioral malfunctions were obvious in all mice.Focal cerebral infarction was detected in ischemic hemispheres,glutamate receptor 1α expression increased,and glutamate transporter 1 expression decreased in the ischemic hemisphere (P〈 0.05).Compared with the model group,neurological behavioral functions significantly improved,cerebral infarction volume was significantly reduced (P〈 0.05),glutamate receptor 1α expression was significantly decreased,and glutamate transporter 1 expression was increased in the cromakalim group (P 〈 0.05).CONCLUSION:Improved neurological function and reduced cerebral infarction volume in rats through the preventive use of cromakalim could be related to decreased glutamate receptor 1α expression and enhanced glutamate transporter 1 expression.
基金the National Natural Science Foundation of China,No.30500575,30770673,81070998Scientific Research Foundation for the Returned Overseas Chinese Scholars,State Education MinistryTechnology Plan of Shaanxi Province,No.2009K01-80
文摘Metabotropic glutamate receptor 5 (mGluR5) is expressed by neurons in zones of active neurogenesis and is involved in the development of neural stem cells in vivo and in vitro. We examined the expression of mGluR5 in the cortex and hippocampus of rats during various prenatal and postnatal periods using immunohistochemistry. During prenatal development, mGluR5 was pdmadly localized to neuronal somas in the forebrain. During early postnatal periods, the receptor was mainly present on somas in the cortex, mGluR5 immunostaining was visible in apical dendrites and in the neuropil of neurons and persisted throughout postnatal development. During this period, pyramidal neurons were strongly labeled for the receptor. In the hippocampal CA1 region, mGluR5 immunoreactivity was more intense in the stratum oriens, stratum radiatum, and lacunosum moleculare at P0, P5 and P10 relative to P60. mGluR5 expression increased significantly in the molecular layer and decreased significantly in the granule cell layer of the dentate gyrus at P5, P10 and P60 in comparison with P0. Furthermore, some mGluR5-positive cells were also bromodeoxyuridine- or NeuroD-positive in the dentate gyrus at P14. These results demonstrate that mGluR5 has a differential expression pattern in the cortex and hippocampus during early growth, suggesting a role for this receptor in the control of domain specific brain developmental events.
基金supported by the National Natural Science Foundation of China,No.30471934
文摘Traumatic brain injury causes gene expression changes in different brain regions. Occurrence and development of traumatic brain injury are closely related, involving expression of three factors, namely cyclooxygenase-2, glutamate receptor-2, and platelet activating factor receptor. However, little is known about the correlation of these three factors and brain neuronal injury. In this study, primary cultured rat hippocampal neurons were subjected to fluid percussion injury according to Scott’s method, with some modifications. RT-PCR and semi-quantitative immunocytochemical staining was used to measure the expression levels of cyclooxygenase-2, glutamate receptor-2, and platelet activating factor receptor. Our results found that cyclooxygenase-2 expression were firstly increased post-injury, and then decreased. Both mRNA and protein expression levels reached peaks at 8 and 12 hours post-injury, respectively. Similar sequential changes in glutamate receptor 2 were observed, with highest levels mRNA and protein expression at 8 and 12 hours post-injury respectively. On the contrary, the expressions of platelet activating factor receptor were firstly decreased post-injury, and then increased. Both mRNA and protein expression levels reached the lowest levels at 8 and 12 hours post-injury, respectively. Totally, our findings suggest that these three factors are involved in occurrence and development of hippocampal neuronal injury.
基金supported by grants from the National Natural Science Foundation of China,No.81371320the Project for Young and Middle-Aged Talents of Fujian Health Care System,No.2013-ZQN-JC-29
文摘The human glutamate receptor delta 2 gene (GRID2) shares 90%homology with the orthologous mouse gene. The mouse Grid2 gene is involved with functions of the cerebellum and sponta-neous mutation of Grid2 leads to a spinocerebellar ataxia-like phenotype. To investigate whether such mutations occur in humans, we screened for mutations in the coding sequence of GRID2 in 24 patients with familial or sporadic spinocerebellar ataxia and in 52 normal controls. We de-tected no point mutations or insertion/deletion mutations in the 16 exons of GRID2. However, a polymorphic 4 nucleotide deletion (IVS5-121_-118 GAGT) and two single nucleotide polymor-phisms (c.1251G〉T and IVS14-63C〉G) were identiifed. The frequency of these polymorphisms was similar between spinocerebellar ataxia patients and normal controls. These data indicate that spontaneous mutations do not occur in GRID2 and that the incidence of spinocerebellar ataxia in humans is not associated with GRID2 mutation or polymorphisms.
基金the National Natural Science Foundation of China, No. 30470555, 30571909, 30870808the Natural Science Foundation of Jiangsu Province, No. BK2007509Natural Science Foundation for Colleges and Universities in Jiangsu Province, No. 07KJB320103
文摘BACKGROUND: Developmental seizures are pathologically characterized by regenerative sprouting of hippocampal mossy fibers rich in Zn^2+. Zn^2+ metabolism in the mossy fiber pathway, and Zn^2+ accumulation in presynaptic membrane vesicles, are dependent on zinc transporter 1 (ZnT1) and glutamate receptor subunit 2 (GluR2). OBJECTIVE: To investigate the effects of long-term recurrent neonatal seizure, in the presence and absence of physical exercise, on the developmental expression of hippocampal zinc transporter 1 (ZnT1) and GluR2, and on cognitive function in rats. DESIGN, TIME AND SETTING: Based on behavioral examination and molecular biological research, a randomized, controlled animal experiment was performed at the Department of Neurobiology, Medical College of Soochow University, between January 2007 and April 2008. MATERIALS: Twenty-one 6-day-old Sprague Dawley rats of either gender were employed in this study. ZnT1 mRNA in situ hybridization kit was provided by Tianjin Haoyang Biological Manufacture Co.,Ltd., China. Rabbit anti-GluR2 was purchased from Santa Cruz Biotech, Inc, USA. METHODS: Rats were randomly divided into a recurrent seizure group (n = 11) and a control group (n = 10). In the recurrent seizure group, 30-minute seizure was induced by flurothyl gas inhalation for a total of 6 consecutive days. Rats from the control group underwent experimental procedures similar to the recurrent seizure group, with the exception of flurothyl gas inhalation. Thirty minutes of treadmill exercise was performed daily by all rats at postnatal days 51–56. MAIN OUTCOME MEASURES: At postnatal day 82, rat hippocampal tissue was harvested for analysis of hippocampal ZnT1 and GluR2 expression by in situ hybridization and immunohistochemistry, respectively. Rat learning and memory capabilities were examined using the Y-maze test. RESULTS: In the recurrent seizure group, the gray scale value of ZnT1 in situ hybridization positive neurons in the hippocampal CA3 region was significantly greater (P 〈 0.05), while the gray scale value of GluR2 immunoreactive neurons in the hippocampal hilus and dentate gyrus was significantly lower (P 〈 0.05), than in the control group. At postnatal days 29–35, numbers of trials to criteria for successful learning were greater in the recurrent seizure group than in the control group (P 〈 0.05); at postnatal days 61–67, the numbers of trials to criteria for successful learning were similar between the two groups (P 〉 0.05). At postnatal days 29–35 and 61–67, there was no significant difference in memory capability between the recurrent seizure and control groups (P 〉 0.05). CONCLUSION: Physical exercise likely improves the learning deficits caused by recurrent neonatal seizure in rats during brain development by modulating ZnT1 and GluR2 expression.
文摘The present study established a rat cortical neuronal model of in vitro mechanical injury. At 30 minutes after injury, the survival rate of the injured cortical neurons was decreased compared with normal neurons, and was gradually decreased with aggravated degree of injury. Reverse transcription-polymerase chain reaction results showed that at 1 hour after injury, there was increased expression of metabotropic glutamate receptor la in cortical neurons. Immunohistochemical staining results showed that at 30 minutes after injury, the number of metabotropic glutamate receptor 1a-positive cells increased compared with normal neurons. At 12 hours after injury, lactate dehydrogenase activity in the (RS)-l-aminoindan-1, 5-dicarboxylic acid (AIDA)-treated injury neurons was si[jnificantly decreased than that in the pure injury group. At 1 hour after injury, intracellular free Ca"+ concentration was markedly decreased in the AIDA-treated injury neurons than that in the pure injury neurons. These findings suggest that after mechanical injury to cortical neurons, metabotropic glutamate receptor la expression increased. The resulting increase in intracellular free Ca2+ concentration was blocked by AIDA, indicating that AIDA exhibits neuroprotective effects after mechanical injury.
文摘The diffuse brain injury model was conducted in Sprague-Dawley rats, according to Marmarou's free-fall attack. The water content in brain tissue, expression of metabotropic glutamate receptor la mRNA and protein were significantly increased after injury, reached a peak at 24 hours, and then gradually decreased. After treatment with the competitive antagonist of metabotropic glutamate receptor la, (RS)-l-aminoindan-1,5-dicarboxylic acid, the water content of brain tissues decreased between 12-72 hours after injury, and neurological behaviors improved at 2 weeks. These experimental findings suggest that the 1-aminoindan-1, 5-dicarboxylic acid may result in marked neuroprotection against diffuse brain injury.
文摘Dopaminergic neurotoxicity is characterized by damage and death of dopaminergic neurons.Parkinson's disease(PD)is a neurodegenerative disorder that primarily involves the loss of dopaminergic neurons in the substantia nigra.Therefore,the study of the mechanisms,as well as the search for new targets for the prevention and treatment of neurodegenerative diseases,is an important focus of modern neuroscience.PD is primarily caused by dysfunction of dopaminergic neurons;however,other neurotransmitter systems are also involved.Research reports have indicated that the glutamatergic system is involved in different pathological conditions,including dopaminergic neurotoxicity.Over the last two decades,the important functional interplay between dopaminergic and glutamatergic systems has stimulated interest in the possible role of metabotropic glutamate receptors(mGluRs)in the development of extrapyramidal disorders.However,the specific mechanisms driving these processes are presently unclear.The participation of the universal neuronal messenger nitric oxide(NO)in the mechanisms of dopaminergic neurotoxicity has attracted increased attention.The current paper aims to review the involvement of mGluRs and the contribution of NO to dopaminergic neurotoxicity.More precisely,we focused on studies conducted on the rotenone-induced PD model.This review is also an outline of our own results obtained using the method of electron paramagnetic resonance,which allows quantitation of NO radicals in brain structures.
基金This study was funded by grants from AFA Forsakring(M.P.).
文摘Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system.However,it is not clear the mechanism by which mast cells communicate with peripheral nerves.We previously found that mast cells located within healing tendons can express glutamate receptors,raising the possibility that mast cells may be sensitive to glutamate signaling.To evaluate this hypothesis,we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type(NMDAR1,NMDAR2A,and NMDAR2B)and the metabotropic type(mGluR2 and mGluR7)at both the mRNA and protein levels.The binding of glutamate to glutamate receptors on the mast cell surface was confirmed.Further,glutamate had extensive effects on gene expression in the mast cells,including the upregulation of proinflammatory components such as IL-6 and CCL2.Glutamate also induced the upregulation of transcription factors,including Egr2,Egr3 and,in particular,FosB.The extensive induction of FosB was confirmed by immunofluorescence assessment.Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate,supporting the supposition of a functional glutamate–glutamate receptor axis in mast cells.Finally,we provide in vivo evidence supporting a functional glutamate–glutamate receptor axis in the mast cells of injured tendons.Together,these findings establish glutamate as an effector of mast cell function,thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.
文摘Neuroadaptations of glutamatergic transmission in the limbic reward circuitry are linked to persistent drug addiction.Accumulating data have demonstrated roles of ionotropic glutamate receptors and groupⅠandⅡmetabotropic glutamate receptors(mGluRs)in this event.Emerging evidence also identifies Gαi/o-coupled groupⅢmGluRs(mGluR4/7/8 subtypes enriched in the limbic system)as direct substrates of drugs of abuse and active regulators of drug action.Auto-and heteroreceptors of mGluR4/7/8 reside predominantly on nerve terminals of glutamatergic corticostriatal and GABAergic striatopallidal pathways,respectively.These presynaptic receptors regulate basal and/or phasic release of respective transmitters to maintain basal ganglia homeostasis.In response to operant administration of common addictive drugs,such as psychostimulants(cocaine and amphetamine),alcohol and opiates,limbic groupⅢmGluRs undergo drastic adaptations to contribute to the enduring remodeling of excitatory synapses and to usually suppress drug seeking behavior.As a result,a loss-of-function mutation(knockout)of individual groupⅢreceptor subtypes often promotes drug seeking.This review summarizes the data from recent studies on three groupⅢreceptor subtypes(mGluR4/7/8)expressed in the basal ganglia and analyzes their roles in the regulation of dopamine and glutamate signaling in the striatum and their participation in the addictive properties of three major classes of drugs(psychostimulants,alcohol,and opiates).
基金supported by grants from the National Natural Science Foundation of China(81070998)the Youth Fund of the College of Medicine,Xi'an Jiaotong University(YQN0802)the Fundamental Research Funds for the Central Universities (xjj2011022)
文摘Objective Metabotropic glutamate receptor 5 (mGluR5) is concentrated in zones of active neurogenesis in the prenatal and postnatal rodent brain and plays an important role in the regulation of neurogenesis. However, little is known about mGluR5 in the prenatal human brain. Here, we aimed to explore the expression pattern and cellular distribution of mGluR5 in human fetal hippocampus. Methods Thirty-four human fetuses were divided into four groups according to gestational age: 9-11, 14-16, 22-24 and 32-36 weeks. The hippocampus was dissected out and prepared. The protein and mRNA expression of mGluR5 were evaluated by Western blot and immunohistochemistry or real-time PCR. The cellular distribution of mGluR5 was observed with double-labeling immunofluorescence. Results Both mGluR5 mRNA and protein were detected in the prenatal human hippocampus by real-time PCR and immunoblotting, and the expression levels increased gradually over time. The immunohistochemistry results were consistent with immunoblotting and showed that mGluR5 immunoreactivity was mainly present in the inner marginal zone (IMZ), hippocampal plate (HP) and ventricular zone (VZ). The double-labeling immunoftuorescence showed that mGluR5 was present in neural stem cells (nestin-positive), neuroblasts (DCX-positive) and mature neurons (NeuN-positive), but not in typical astrocytes (GFAP- positive). The cells co-expressing mGluR5 and nestin were mainly located in the IMZ, HP and subplate at 11 weeks, all layers at 16 weeks, and CA 1 at 24 weeks. As development proceeded, the number of mGluR5/nestin double-positive cells decreased gradually so that there were only a handful of double-labeled cells at 32 weeks. However, mGluR5/DCX double-positive cells were only found in the HP, IZ and IMZ at 11 weeks. Conclusion The pattern ofmGluR5 expression by neural stern/progenitor cells, neuroblasts and neurons provides important anatomical evidence for the role of mGluR5 in the regulation of human hippocampal development.
基金Project (No. 29725205) supported by the National Natural Science FoundatiOn of China
文摘The synthetic studies for some known modulators of metabotropic glutamate receptors (mGluRs) such as (S)-αM4CPG, (1S,3R)-ACPD, L-CCG-I are described. Based on the structure of αM4CPG several new conformationally constrained analogues are design ed and synthesized. Among them APICA is a selective antagonist for group II mGluRs. Also, a new benzolactam-V8 analogue is found to have better isoform-selectivity for protein kine C family. Three different protocols for synthesizing benzolactam-VS analogues are developed to meet the requirement for delivering more analogues to test.
基金This research was funded by the Natural Science Foundation of Shandong Province of China(ZR2022MC144).
文摘Grapes,one of the oldest tree species globally,are rich in vitamins.However,environmental conditions such as low temperature and soil salinization significantly affect grape yield and quality.The glutamate receptor(GLR)family,comprising highly conserved ligand-gated ion channels,regulates plant growth and development in response to stress.In this study,11 members of the VvGLR gene family in grapes were identified using whole-genome sequence analysis.Bioinformatic methods were employed to analyze the basic physical and chemical properties,phylogenetic trees,conserved domains,motifs,expression patterns,and evolutionary relationships.Phylogenetic and collinear analyses revealed that the VvGLRs were divided into three subgroups,showing the high conservation of the grape GLR family.These members exhibited 2 glutamate receptor binding regions(GABAb and GluR)and 3-4 transmembrane regions(M1,M2,M3,and M4).Real-time quantitative PCR analysis demonstrated the sensitivity of all VvGLRs to low temperature and salt stress.Subsequent localization studies in Nicotiana tabacum verified that VvGLR3.1 and VvGLR3.2 proteins were located on the cell membrane and cell nucleus.Additionally,yeast transformation experiments confirmed the functionality of VvGLR3.1 and VvGLR3.2 in response to low temperature and salt stress.Thesefindings highlight the significant role of the GLR family,a highly conserved group of ion channels,in enhancing grape stress resistance.This study offers new insights into the grape GLR gene family,providing fundamental knowledge for further functional analysis and breeding of stress-resistant grapevines.
基金the Scientific and Technological Research Project of Jiangxi Provincial Public Health Bureau,No.20071090
文摘BACKGROUND: Injection of glutamate (Glu) in normal animals can cause neuronal c-Fos expression; however, whether Glu can induce spinal neuronal c-Fos expression in pain models is unclear. OBJECTIVE: To examine the effects of intraplantar and intrathecal injection of Glu on c-Fos expression in the L5 spinal cord dorsal horn Ⅰ/Ⅱ and Ⅲ/Ⅳ layers after spinal nerve ligation, and to study the effects of the N-methyI-D-aspartic acid (NMDA) receptor antagonist, D-2-amino-5-phosphonopentanoate (D-AP5), and a selective group I mGluR antagonist, 7-hydroyiminocyclo propan[a]chromen-lacarboxylic acid ethyl ester (cpccoEt). DESIGN, TIME AND SETTING: A randomized, controlled animal study was performed at the Department of Pharmacology, Oral Anatomy, and Neurobiology, Osaka University Graduate School of Dentistry, from December 2005 to December 2006. MATERIALS: Glu (5 μmol), D-AP5 (50 nmot) and cpccoEt (250 nmol) were provided by Wako Pure Chemical Industries, Osaka, Japan, and diluted in saline (50 μL). The pH of all solutions was adjusted to 7.4. METHODS: Twelve rats were randomly divided into sham operation (n = 6) and spinal nerve ligation (SNL; n = 6) groups for behavioral assessments of neuropathic pain after ligation surgery of the left L5-6 nerve segment. Another 60 rats were randomly divided into sham operation, SNL, saline-intraplantar, saline-intrathecal, Glu-intraplantar, Glu-intrathecal, D-AP5-intrathecal, Glu-D-AP5-intrathecal, cpccoEt-intrathecal, and Glu-cpccoEt-intrathecal groups, with 6 rats in each group. All groups except sham operation group received a similar SNL. On day 14, rats received a 50-μL injection of saline, Glu, D-AP5, and/or cpccoEt into the left intraplantar or intrathecal L5-4 segments. MAIN OUTCOME MEASURES: The number of c-Fos positive neurons in both Ⅰ/Ⅱ and Ⅲ/Ⅳ spinal layers at L6 was observed using immunohistochemistry 2 hours after administration. RESULTS: (1) SNL increased the level of c-Fos expression in two sides of the spinal cord, particularly on Ⅲ/Ⅳ spinal layers of the ligated side. (2) Intraplantar or intrathecal administration of saline significantly increased the c-Fos labeled neurons in Ⅰ/Ⅱ spinal layers of the ligated side, compared with SNL alone (P 〈 0.01). (3) Intraplantar Glu (5 μmol) increased the number of c-Fos positive neurons in Ⅰ/Ⅱ spinal layers compared with intraplantar saline (P〈 0.01). (4) The number of c-Fos neurons in Ⅰ/Ⅱ spinal layers on both the ipsilateral and contralateral side after intraplantar Glu was lower than intrathecal Glu (P〈 0.01), with a 3-fold higher induction by intrathecal Glu. (5) Co-administration of D-AP5 or cpccoEt reduced the effects of intrathecal Glu (P 〈 0.01). CONCLUSION: Intrathecal Glu increases c-Fos expression more than intraplantar Glu. Antagonists of NMDA and group I mGluRs block this effect.
基金Supported by Canadian Institutes of Health Research Grant,No.TGS-1092194-Year Fellowship from the University of British Columbia.
文摘Insufficient sleep has been correlated to many physiological and psychoneurological disorders.Over the years,our understanding of the state of sleep has transcended from an inactive period of rest to a more active state involving important cellular and molecular processes.In addition,during sleep,electrophysiological changes also occur in pathways in specific regions of the mammalian central nervous system(CNS).Activity mediated synaptic plasticity in the CNS can lead to long-term and sometimes permanent strengthening and/or weakening synaptic strength affecting neuronal network behaviour.Memory consolidation and learning that take place during sleep cycles,can be affected by changes in synaptic plasticity during sleep disturbances.G-protein coupled receptors(GPCRs),with their versatile structural and functional attributes,can regulate synaptic plasticity in CNS and hence,may be potentially affected in sleep deprived conditions.In this review,we aim to discuss important functional changes that can take place in the CNS during sleep and sleep deprivation and how changes in GPCRs can lead to potential problems with therapeutics with pharmacological interventions.
基金supported by NIH/NCI ROICA140988-01 to JWpartially supported by Chinese Scholar Council to HY。
文摘Glutamine and glutamate are major bioenergy substrates for normal and cancer cell growth.Cancer cells need more biofuel than normal tissues for energy supply,anti-oxidation activity and biomass production.Genes related to metabolic chains in many cancers are somehow mutated,which makes cancer cells more glutamate dependent.Meanwhile,glutamate is an excitatory neurotransmitter for conducting signals through binding with different types of receptors in central neuron system.Interestingly,increasing evidences have shown involvement of glutamate signaling,guided through their receptors,in human malignancy.Dysregulation of glutamate transporters,such as excitatory amino acid transporter and cystine/glutamate antiporter system,also generates excessive extracellular glutamate,which in turn,activates glutamate receptors on cancer cells and results in malignant growth.These features make glutamate an attractive target for anti-cancer drug development with some glutamate targeted but blood brain barrier impermeable anti-psychosis drugs under consideration.We discussed the relevant progressions and drawbacks in this field herein.
基金supported by a grant from the National Natural Science Foundation of China (No.30770753)
文摘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 D1 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, pallidal GABA, and subthalamic GABA, which remained the same as that in denervation group. However, chronic treatment reversed the increase of nigral 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.