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
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 rec...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 1α 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
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
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 effect...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/Ⅱand Ⅲ/Ⅳ layers after spinal nerve ligation,and to study the effects of the N-methyl-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-1a-carboxylic 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 nmol) 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 L5-6 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/Ⅱspinal 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
Objective To study the effect of glutamate on the expression of vascular endothelial growth factor (VEGF) mRNA and protein in cultured rat astrocytes. Methods Cultured rat astrocytes were randomly divided into 6 group...Objective To study the effect of glutamate on the expression of vascular endothelial growth factor (VEGF) mRNA and protein in cultured rat astrocytes. Methods Cultured rat astrocytes were randomly divided into 6 groups:control group (C),glutamate group (G),QA group (Q),DCG-IV group (D),L-AP4 group (L) and glutamate+MCPG group (G+M). Cells were cultured under nomoxic condition (95% air,5% CO2). RT-PCR and ELISA methods were used to detect the expression of VEGF mRNA and protein in cultured astrocytes,respectively. G+M group was preincubated with 1mM MCPG for 30 min prior to the stimulation with glutamate. There were 7 time points at 0,4,8,12,16,24 and 48 h in each group except G+M group. Results The expression of VEGF mRNA and protein did not differ significantly among D group,L group and C group. Different from that in C group,the expression of VEGF mRNA and protein could be enhanced both in a dose-dependent and time-dependent manner in G group and Q group. Meanwhile,the enhanced expression of VEGF mRNA and protein in G group was completely suppressed by MCPG after 24 h. Conclusion Glutamate can increase the expression of VEGF mRNA and protein in cultured astrocytes,which may be due to the activation of group I metabotropic glutamate receptors in astrocytes.展开更多
As the global population ages,research on the pathogenesis and treatment options for older patients with dementia has become increasingly important.Vascular dementia(VaD),the second most frequent type of dementia,is c...As the global population ages,research on the pathogenesis and treatment options for older patients with dementia has become increasingly important.Vascular dementia(VaD),the second most frequent type of dementia,is characterized by vascular impairment caused by inadequate blood supply to the brain.VaD is a complex neurological disorder involving multiple cells and signaling pathways,and its prevention and treatment pose clinical challenges with significant behavioral implications.Glutamate,the most abundant amino acid in the brain,plays a critical role as an excitatory neurotransmitter,impacting cognitive function,learning,and memory.Abnormal glutamate metabolism has been closely linked to dementia,and reduced blood flow to the brain can lead to excessive glutamate accumulation,resulting in neuronal death.This article highlights the connection between VaD and glutamate metabolism,aiming to identify better methods for preventing and treating VaD via regulating glutamate metabolism.展开更多
Cognitive decline in Alzheimer’s disease correlates with the extent of tau pathology,in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the...Cognitive decline in Alzheimer’s disease correlates with the extent of tau pathology,in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus.Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-βor long-term depression,a form of synaptic weakening involved in learning and memory,share similar mechanisms.Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging.Conversely,certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau,in particular,phosphorylation at residue Ser396.Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau(hyper)phosphorylation.We first summarize experimental evidence regarding tau-long-term depression interactions,followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer’s disease.Finally,we conclude with some thoughts and perspectives on future research about these interactions.展开更多
OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depre...OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depression,but more and more evidence indicates that glutamatergic transmission may be the key factor leading to the occurrence of depression. However,the role of the membrane expression and regulation of glutamate receptors in the development of depression has not been elucidated. To address this issue,we have done series of experiments. METHODS Different methods and techniques,such as behavior,morphology,molecular biology and electrophysiology,were applied to investigate the impact of glutamate receptors and their subunits in the regulation of synaptic plasticity and the mechanism in depressive animal models. RESULTS Chronic social defeat stress(CSDS) can induce depressive behaviors in wildtype(WT) mice but not caspase-1 knockout(KO) mice. Further experiments showed that,in WT mice,CSDS induced a significant decrease in the membrane expression levels of the GluR1 and GluR2 subunits of AMPA receptors,the amplitudes of m EPSC in hippocampal CA1,meanwhile the long-term potentiation(LTP) at hippocampus SC-CA1 pathway was also impaired. Oppositely,this CSDS-induced reduction of the membrane expression of AMPA receptors was prevented by the knockout of caspase-1 or caspase-1 inhibitor,in which the expression of GluA1 and GluA2 were upregulated from(60.2±3.4)% and(63.9±3.7)% to(120.1±5.9)%and(112.6±9.6)%,respectively,while the total protein level of AMPA receptor subunits were not affected.On the other hand,a chronic intracerebroventricular injection of IL-1β,a downstream signal molecule of caspase-1,could induce depression-and anxiety-like behaviors in caspase-1 KO mice. CONCLUSION The caspase-1 can mediate the stress-induced depression-like behaviors by down-regulation of the membrane expression of AMPA receptors in hippocampus,the inhibition or knock-out of caspase-1can increase the expression of AMPA receptors in the membrane,thus reversing the depression-like behavior. Caspase-1 may serve as new target for depression therapy.展开更多
Parkinson's disease(PD) is one of the most debilitating brain diseases. Despite the availability of symptomatic treatments, response towards the health of PD patients remains scarce. To fulfil the medical needs of...Parkinson's disease(PD) is one of the most debilitating brain diseases. Despite the availability of symptomatic treatments, response towards the health of PD patients remains scarce. To fulfil the medical needs of the PD patients, an efficacious and etiological treatment is required. In this review, we have compiled the information covering limitations of current therapeutic options in PD, novel drug targets for PD, and finally, the role of some critical beneficial natural products to control the progression of PD.展开更多
Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage.Secondary damage presents the greatest...Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage.Secondary damage presents the greatest challenge for medical staff;however,there are currently few effective therapeutic targets for secondary damage.Homer proteins are postsynaptic scaffolding proteins that have been implicated in ischemic and traumatic insults to the central nervous system.Homer signaling can exert either positive or negative effects during such insults,depending on the specific subtype of Homer protein.Homer 1b/c couples with other proteins to form postsynaptic densities,which form the basis of synaptic transmission,while Homer 1a expression can be induced by harmful external factors.Homer 1c is used as a unique biomarker to reveal alterations in synaptic connectivity before and during the early stages of apoptosis in retinal ganglion cells,mediated or affected by extracellular or intracellular signaling or cytoskeletal processes.This review summarizes the structural features,related signaling pathways,and diverse roles of Homer proteins in physiological and pathological processes.Upregulating Homer 1a or downregulating Homer 1b/c may play a neuroprotective role in secondary brain injuries.Homer also plays an important role in the formation of photoreceptor synapses.These findings confirm the neuroprotective effects of Homer,and support the future design of therapeutic drug targets or gene therapies for ischemic and traumatic brain injuries and retinal disorders based on Homer proteins.展开更多
Alzheimer’s disease(AD),also defined as a tauopathology,is a common neurodegenerative disease.Hyper-phosphorylation,cleavage or truncation,and aggregation of tau contribute to AD.Thus,targeting the post-translational...Alzheimer’s disease(AD),also defined as a tauopathology,is a common neurodegenerative disease.Hyper-phosphorylation,cleavage or truncation,and aggregation of tau contribute to AD.Thus,targeting the post-translational modifications on tau may be a therapeutic strategy to treat AD.This study understood how cornel iridoid glycoside(CIG)affects tau post-translational modifications and synaptic abnormalities.The 10-month old P301S tau transgenic mice were given CIG at 100 and 200 mg/kg every day orally for 1 month.Hyperphosphorylated and truncated tau,synapse-associated proteins and glutamatergic receptors were all detected using Western blotting.The interactions between Morroniside(MOR)or Loganin(LOG)and tau were detected using Autodock and Surface Plasmon Resonance(SPR).The effects of CIG on the aggregation of tau were investigated using a cell-free system.CIG attenuated tau hyperphosphorylation at Thr205,Ser212,Ser262,Thr231 and Ser235(AT180),but had no effect on tau truncation in the brains of 10-month old P301S mice.Binding free energies and interactions revealed that MOR and LOG bound with tau.We also found that CIG upregulated synapse-associated proteins such as PSD-95,syntaxin1A and synaptotagmin.In addition,CIG restored N-methyl-D-aspartic acid receptor and glutamate receptor levels.CIG improves post-translational modification of tau as well as synaptic abnormalities.The data presented here reveal that CIG may be used in the treatment of AD.展开更多
We investigated the pharmacokinetics of caroverine in the perilymph,cerebrospinal fluid and plasma after systemic and local administrations in guinea pigs by using high-performance liquid chromatography.Auditory brain...We investigated the pharmacokinetics of caroverine in the perilymph,cerebrospinal fluid and plasma after systemic and local administrations in guinea pigs by using high-performance liquid chromatography.Auditory brainstem responses were measured to evaluate auditory functional effect.The results showed that local application was a both safe and efficient method.We further reviewed literature and pinpointed that the round window is effectively local drug delivery means for future inner ear treatment.展开更多
OBJECTIVE AMPA-subtype iono⁃tropic glutamate receptors(iGluRs)mediate fast excitatory synaptic transmission in the mammali⁃an central nervous system(CNS).It plays the key role in many central nerves disorder such as e...OBJECTIVE AMPA-subtype iono⁃tropic glutamate receptors(iGluRs)mediate fast excitatory synaptic transmission in the mammali⁃an central nervous system(CNS).It plays the key role in many central nerves disorder such as epilepsy,depression and schizophrenia.Star⁃gazin(STZ,also named TARP-γ2),as the first TARPs found in CNS,potentiates AMPAR activity by attenuating deactivation and desensitization,enhancing recovery from desensitization,and facilitating agonist affinity and efficacy.However,it is still not fully understanding howγ-2 modu⁃late AMPAR gating.METHODS AND RESULTS The desensitization for different mutation of AMPAR andγ-2 was compared.It was shown that the electric attraction was involved in the interaction of AMPAR andγ-2.In addition,the interaction of KGK motif in ligand binding domain and pre-M1 chain of AMPAR and EX1 ofγ-2 modulate AMPAR opening and desensitization.Substitution of these charged residues had sur⁃prisingly effects on AMPAR desensitization kinet⁃ics.CONCLUSION The electric attraction has two impacts on the channels gating process the first destablizing the receptor closed state and enabling the channel opening,the second pro⁃moting the channels entering desensitization state upon the channel opening.展开更多
Alcohol-related liver disease(ALD)became an important health issue worldwide.Following chronic alcohol consumption,the development of ALD might be caused by metabolic and immunologic factors,such as reactive oxygen sp...Alcohol-related liver disease(ALD)became an important health issue worldwide.Following chronic alcohol consumption,the development of ALD might be caused by metabolic and immunologic factors,such as reactive oxygen species(ROS)and pro-inflammatory cytokines.For example,hepatic cytochrome P4502E1 enzyme increases ROS production and stimulates de novo lipogenesis after alcohol exposure.In addition,damage-and pathogen-associated molecular patterns stimulate their specific receptors in nonparenchymal cells,including Kupffer cells,hepatic stellate cells(HSCs),and lymphocytes,which result in hepatocyte death and infiltration of pro-inflammatory cells(e.g.,neutrophils and macrophages)in the liver.Moreover,our studies have suggested the novel involvement of neurologic signaling pathways(e.g.,endocannabinoid and glutamate)through the metabolic synapse between hepatocytes and HSCs in the development of alcohol-related hepatic steatosis.Additionally,agouti-related protein and beta2-adrenergic receptors aggravate hepatic steatosis.Furthermore,organ-crosstalk has emerged as a critical issue in ALD.Chronic alcohol consumption induces dysbiosis and barrier disruption in the gut,leading to endotoxin leakage into the portal circulation,or lipolysis-mediated transport of triglycerides from the adipose tissue to the liver.In summary,this review addresses multiple pathogeneses of ALD,provides novel neurologic signaling pathways,and emphasizes the importance of organ-crosstalk in the development of ALD.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 1α 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.
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/Ⅱand Ⅲ/Ⅳ layers after spinal nerve ligation,and to study the effects of the N-methyl-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-1a-carboxylic 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 nmol) 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 L5-6 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/Ⅱspinal 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 the National Natural Science Foundation of China (N0.30770673)
文摘Objective To study the effect of glutamate on the expression of vascular endothelial growth factor (VEGF) mRNA and protein in cultured rat astrocytes. Methods Cultured rat astrocytes were randomly divided into 6 groups:control group (C),glutamate group (G),QA group (Q),DCG-IV group (D),L-AP4 group (L) and glutamate+MCPG group (G+M). Cells were cultured under nomoxic condition (95% air,5% CO2). RT-PCR and ELISA methods were used to detect the expression of VEGF mRNA and protein in cultured astrocytes,respectively. G+M group was preincubated with 1mM MCPG for 30 min prior to the stimulation with glutamate. There were 7 time points at 0,4,8,12,16,24 and 48 h in each group except G+M group. Results The expression of VEGF mRNA and protein did not differ significantly among D group,L group and C group. Different from that in C group,the expression of VEGF mRNA and protein could be enhanced both in a dose-dependent and time-dependent manner in G group and Q group. Meanwhile,the enhanced expression of VEGF mRNA and protein in G group was completely suppressed by MCPG after 24 h. Conclusion Glutamate can increase the expression of VEGF mRNA and protein in cultured astrocytes,which may be due to the activation of group I metabotropic glutamate receptors in astrocytes.
基金National Natural Science Foundation of China,Grant/AwardNumbers:82204376,82360710The Basic Ability Enhancement Program for Young and Middle-aged Teachers of Guangxi,Grant/AwardNumber:2022KY0505+2 种基金Fundof Guangxi ResearchandInnovationBasefor Basic and Clinical Application of Nerve Injury and RepairProject,Grant/AwardNumber:ZY21195042ResearchProject Fund forDrug Safety of Guangxi Food and Drug Administration,Grant/AwardNumber:GUIYA JINKESUZISHU[2023]No.008Guangxi Science and Technology Project,Grant/AwardNumber:AD171290015。
文摘As the global population ages,research on the pathogenesis and treatment options for older patients with dementia has become increasingly important.Vascular dementia(VaD),the second most frequent type of dementia,is characterized by vascular impairment caused by inadequate blood supply to the brain.VaD is a complex neurological disorder involving multiple cells and signaling pathways,and its prevention and treatment pose clinical challenges with significant behavioral implications.Glutamate,the most abundant amino acid in the brain,plays a critical role as an excitatory neurotransmitter,impacting cognitive function,learning,and memory.Abnormal glutamate metabolism has been closely linked to dementia,and reduced blood flow to the brain can lead to excessive glutamate accumulation,resulting in neuronal death.This article highlights the connection between VaD and glutamate metabolism,aiming to identify better methods for preventing and treating VaD via regulating glutamate metabolism.
基金supported by the National Natural Science Foundation of China (U2004134)Zhengzhou University (140/32310295) to NWH+2 种基金by Science Foundation Ireland(19/FFP/6437 and 14/IA/2571) to MJRa scholarship granted by the China Scholarship Council (CSC20200704504 7) to YY
文摘Cognitive decline in Alzheimer’s disease correlates with the extent of tau pathology,in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus.Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-βor long-term depression,a form of synaptic weakening involved in learning and memory,share similar mechanisms.Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging.Conversely,certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau,in particular,phosphorylation at residue Ser396.Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau(hyper)phosphorylation.We first summarize experimental evidence regarding tau-long-term depression interactions,followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer’s disease.Finally,we conclude with some thoughts and perspectives on future research about these interactions.
文摘OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depression,but more and more evidence indicates that glutamatergic transmission may be the key factor leading to the occurrence of depression. However,the role of the membrane expression and regulation of glutamate receptors in the development of depression has not been elucidated. To address this issue,we have done series of experiments. METHODS Different methods and techniques,such as behavior,morphology,molecular biology and electrophysiology,were applied to investigate the impact of glutamate receptors and their subunits in the regulation of synaptic plasticity and the mechanism in depressive animal models. RESULTS Chronic social defeat stress(CSDS) can induce depressive behaviors in wildtype(WT) mice but not caspase-1 knockout(KO) mice. Further experiments showed that,in WT mice,CSDS induced a significant decrease in the membrane expression levels of the GluR1 and GluR2 subunits of AMPA receptors,the amplitudes of m EPSC in hippocampal CA1,meanwhile the long-term potentiation(LTP) at hippocampus SC-CA1 pathway was also impaired. Oppositely,this CSDS-induced reduction of the membrane expression of AMPA receptors was prevented by the knockout of caspase-1 or caspase-1 inhibitor,in which the expression of GluA1 and GluA2 were upregulated from(60.2±3.4)% and(63.9±3.7)% to(120.1±5.9)%and(112.6±9.6)%,respectively,while the total protein level of AMPA receptor subunits were not affected.On the other hand,a chronic intracerebroventricular injection of IL-1β,a downstream signal molecule of caspase-1,could induce depression-and anxiety-like behaviors in caspase-1 KO mice. CONCLUSION The caspase-1 can mediate the stress-induced depression-like behaviors by down-regulation of the membrane expression of AMPA receptors in hippocampus,the inhibition or knock-out of caspase-1can increase the expression of AMPA receptors in the membrane,thus reversing the depression-like behavior. Caspase-1 may serve as new target for depression therapy.
基金supported by UGC Dr.D.S.Kothari Postdoctoral scheme by awarding the fellowship to SNR(Ref.No-F.4-2/2006(BSR)/BL/19-20/0032)。
文摘Parkinson's disease(PD) is one of the most debilitating brain diseases. Despite the availability of symptomatic treatments, response towards the health of PD patients remains scarce. To fulfil the medical needs of the PD patients, an efficacious and etiological treatment is required. In this review, we have compiled the information covering limitations of current therapeutic options in PD, novel drug targets for PD, and finally, the role of some critical beneficial natural products to control the progression of PD.
基金supported by the National Natural Science Foundation of China,Nos.81600738(to FF),81771239(to ZF),81801300(to NS)。
文摘Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage.Secondary damage presents the greatest challenge for medical staff;however,there are currently few effective therapeutic targets for secondary damage.Homer proteins are postsynaptic scaffolding proteins that have been implicated in ischemic and traumatic insults to the central nervous system.Homer signaling can exert either positive or negative effects during such insults,depending on the specific subtype of Homer protein.Homer 1b/c couples with other proteins to form postsynaptic densities,which form the basis of synaptic transmission,while Homer 1a expression can be induced by harmful external factors.Homer 1c is used as a unique biomarker to reveal alterations in synaptic connectivity before and during the early stages of apoptosis in retinal ganglion cells,mediated or affected by extracellular or intracellular signaling or cytoskeletal processes.This review summarizes the structural features,related signaling pathways,and diverse roles of Homer proteins in physiological and pathological processes.Upregulating Homer 1a or downregulating Homer 1b/c may play a neuroprotective role in secondary brain injuries.Homer also plays an important role in the formation of photoreceptor synapses.These findings confirm the neuroprotective effects of Homer,and support the future design of therapeutic drug targets or gene therapies for ischemic and traumatic brain injuries and retinal disorders based on Homer proteins.
基金This project was supported by grants from National Natural Science Foundation of China(No.81874351 and No 81703729)Beijing Hospitals Authority Ascent Plan of China(No.DFL20190803)National Major Science and Technology Projects of China(No.2015ZX09101-016).
文摘Alzheimer’s disease(AD),also defined as a tauopathology,is a common neurodegenerative disease.Hyper-phosphorylation,cleavage or truncation,and aggregation of tau contribute to AD.Thus,targeting the post-translational modifications on tau may be a therapeutic strategy to treat AD.This study understood how cornel iridoid glycoside(CIG)affects tau post-translational modifications and synaptic abnormalities.The 10-month old P301S tau transgenic mice were given CIG at 100 and 200 mg/kg every day orally for 1 month.Hyperphosphorylated and truncated tau,synapse-associated proteins and glutamatergic receptors were all detected using Western blotting.The interactions between Morroniside(MOR)or Loganin(LOG)and tau were detected using Autodock and Surface Plasmon Resonance(SPR).The effects of CIG on the aggregation of tau were investigated using a cell-free system.CIG attenuated tau hyperphosphorylation at Thr205,Ser212,Ser262,Thr231 and Ser235(AT180),but had no effect on tau truncation in the brains of 10-month old P301S mice.Binding free energies and interactions revealed that MOR and LOG bound with tau.We also found that CIG upregulated synapse-associated proteins such as PSD-95,syntaxin1A and synaptotagmin.In addition,CIG restored N-methyl-D-aspartic acid receptor and glutamate receptor levels.CIG improves post-translational modification of tau as well as synaptic abnormalities.The data presented here reveal that CIG may be used in the treatment of AD.
文摘We investigated the pharmacokinetics of caroverine in the perilymph,cerebrospinal fluid and plasma after systemic and local administrations in guinea pigs by using high-performance liquid chromatography.Auditory brainstem responses were measured to evaluate auditory functional effect.The results showed that local application was a both safe and efficient method.We further reviewed literature and pinpointed that the round window is effectively local drug delivery means for future inner ear treatment.
文摘OBJECTIVE AMPA-subtype iono⁃tropic glutamate receptors(iGluRs)mediate fast excitatory synaptic transmission in the mammali⁃an central nervous system(CNS).It plays the key role in many central nerves disorder such as epilepsy,depression and schizophrenia.Star⁃gazin(STZ,also named TARP-γ2),as the first TARPs found in CNS,potentiates AMPAR activity by attenuating deactivation and desensitization,enhancing recovery from desensitization,and facilitating agonist affinity and efficacy.However,it is still not fully understanding howγ-2 modu⁃late AMPAR gating.METHODS AND RESULTS The desensitization for different mutation of AMPAR andγ-2 was compared.It was shown that the electric attraction was involved in the interaction of AMPAR andγ-2.In addition,the interaction of KGK motif in ligand binding domain and pre-M1 chain of AMPAR and EX1 ofγ-2 modulate AMPAR opening and desensitization.Substitution of these charged residues had sur⁃prisingly effects on AMPAR desensitization kinet⁃ics.CONCLUSION The electric attraction has two impacts on the channels gating process the first destablizing the receptor closed state and enabling the channel opening,the second pro⁃moting the channels entering desensitization state upon the channel opening.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Ministry of Science and ICT,Korean goverment(2021R1A2C3004589,2014M3A9D5A01073556).
文摘Alcohol-related liver disease(ALD)became an important health issue worldwide.Following chronic alcohol consumption,the development of ALD might be caused by metabolic and immunologic factors,such as reactive oxygen species(ROS)and pro-inflammatory cytokines.For example,hepatic cytochrome P4502E1 enzyme increases ROS production and stimulates de novo lipogenesis after alcohol exposure.In addition,damage-and pathogen-associated molecular patterns stimulate their specific receptors in nonparenchymal cells,including Kupffer cells,hepatic stellate cells(HSCs),and lymphocytes,which result in hepatocyte death and infiltration of pro-inflammatory cells(e.g.,neutrophils and macrophages)in the liver.Moreover,our studies have suggested the novel involvement of neurologic signaling pathways(e.g.,endocannabinoid and glutamate)through the metabolic synapse between hepatocytes and HSCs in the development of alcohol-related hepatic steatosis.Additionally,agouti-related protein and beta2-adrenergic receptors aggravate hepatic steatosis.Furthermore,organ-crosstalk has emerged as a critical issue in ALD.Chronic alcohol consumption induces dysbiosis and barrier disruption in the gut,leading to endotoxin leakage into the portal circulation,or lipolysis-mediated transport of triglycerides from the adipose tissue to the liver.In summary,this review addresses multiple pathogeneses of ALD,provides novel neurologic signaling pathways,and emphasizes the importance of organ-crosstalk in the development of ALD.
