亲代谢型谷氨酸受体和相关神经疾病

谷氨酸的过量释放在多种神经系统疾病的发生发展过程中发挥着重要作用。虽然离子型谷氨酸受体拮抗剂在动物模型中取得了一定的治疗效果,但因其同时阻断了正常的兴奋性传递,限制了这类化合物的临床应用;而mG luR s通过突触前机制抑制谷氨酸的释放,有望成为某些神经系统疾病治疗的新靶点。该文就近年来国内外mG luR s在这些神经疾病中的研究进展作一综述。     

脑缺血后谷氨酸及其受体介导的神经细胞损伤及相关药物研究进展

脑缺血损伤涉及多种病理过程,其中兴奋性毒性是关键机制之一。谷氨酸是脑内主要的兴奋性递质,谷氨酸及其受体的病理变化是引起兴奋性毒性的重要病理基础。该文综述了脑缺血后谷氨酸异常释放、谷氨酸受体表达变化及受体后信号传导等病理机制,及以上述机制为靶点的药物研究进展。     

谷氨酸在晕动病发病机制中的作用及相关药物研究

谷氨酸不仅是人和哺乳动物中枢神经系统的基本兴奋性神经递质,也参与外周感觉系统的突触传递。然而,过量谷氨酸引起的谷氨酸受体过度激活导致谷氨酸兴奋性神经毒性。本文对谷氨酸在前庭终器的神经传递和谷氨酸在晕动病中对其的兴奋毒性进行了讨论,并对与谷氨酸神经传递过程相关的抗晕动病药物进行综述。     

超氧阴离子对脑片谷氨酸释放的增强及依布硒的抑制

超氧阴离子对脑片谷氨酸释放的增强及依布硒的抑制易永杨祥良徐辉碧赵西龙１张亨山１秦钰慧１（华中理工大学化学系，武汉４３００７４；１中国预防医学科学院环境卫生监测研究所毒理室，北京１０００２１）兴奋性毒性是神经系统疾病中神经元损伤的一种重要病理机理，其特...     

一氧化氮合酶不同亚型的兴奋性毒性作用

生理状态下,中枢神经系统中的谷氨酸大多位于突触前的囊泡中,在神经细胞除极释放后,也迅速回到囊泡中。然而,在缺血缺氧等病理条件下,谷氨酸过量释放并堆积在细胞外,启动称之为兴奋性毒性的神经细胞死亡。许多神经系统退行性疾病伴随有兴奋性毒性作用。从兴奋性毒性损伤到     

脑缺血时谷氨酸释放机制

谷氨酸是中枢神经系统主要的兴奋性神经递质,在脑缺血造成的神经元损伤过程中发挥重要作用。脑缺血时多种机制参与了谷氨酸释放的的调节,如Ca2+依赖性的出胞式释放、谷氨酸转运体调节的释放、水肿诱发的释放和受体调节的释放等。本文根据现有的文献资料,综述了脑缺血时谷氨酸释放机制。     

囊泡谷氨酸转运体与神经系统疾病

囊泡谷氨酸转运体(vesicular glutamate transporters,VGLUTs)能特异地装载谷氨酸进入突触囊泡并促进释放,它包括3个成员,其中VGLUT1和VGLUT2是谷氨酸能神经元和它们轴突末端高度特异的标志,同时VGLUT1标志着皮质-皮质投射,VGLUT2标志着丘脑-皮层投射。而VGLUT3则会出现在胆碱能中间神经元、5-羟色胺能神经元、海马和皮层中GABA能中间神经元中。VGLUTs的异常会导致兴奋性神经递质谷氨酸的异常,从而诱发多种神经系统疾病。该文综述了VGLUTs的功能障碍与阿尔采末病(Alzheimer’sdisease,AD)、帕金森病(Parkinson’s disease,PD)、精神分裂症、抑郁症、癫痫、耳聋发病的关系的研究进展,为这些疾病的防治提供新的线索。     

谷氨酸代谢变化与脑缺血损伤

在哺乳动物的中枢神经系统（central nervous system，CNS）中，谷氨酸是主要的兴奋性神经递质之一，也是一种潜在的神经毒素，生理状态下谷氨酸合成、分解、摄取和重吸收是一个动态平衡的过程，这种动态平衡一旦遭到破坏，引起的兴奋毒性就可能导致神经细胞的死亡，造成广泛的脑组织病理性损害。现就脑缺血时谷氨酸代谢变化与脑缺血损伤关系的研究进展做如下综述。     

基于谷氨酸的治疗方法：以谷氨酸转运系统为靶点

谷氨酸的作用具有双重性，既是体内主要的兴奋性神经递质，又是潜在的内源性神经毒。为探索新的治疗方法．离子型和代谢型谷氨酸受体在多种中枢神经系统疾病中被广泛研究。但关于其转运蛋白或兴奋性氨基酸转运体（excitatory amino acid transporters，EAATS）的研究仍不多见。近年来。随着多种EAATS亚型被克隆，研发出选择性转运体抑制剂。这为阐明各亚型转运体在调节细胞外谷氨酸稳态中的具体作用提供了重要的研究工具。     

谷氨酸转运体、谷氨酸/胱氨酸转运体与谷氨酸神经细胞毒作用

谷氨酸转运体与谷氨酸／胱氨酸转运体在脑缺血疾病中起重要作用，谷氨酸转运体的结构或功能改变可使细胞间隙的谷氨酸浓度急剧升高，激活NMDA受体产生一系列的表现，同时抑制谷氨酸／胱氨酸转运体对胱氨酸的摄取，介导谷胱苷肽耗竭、氧自由基升高、胞内钙升高、线粒体损伤、细胞色素c释放等神经细胞毒环节，激活半胱天冬酶诱导凋亡。可进一步加重谷氨酸的神经细胞毒作用。     

Non-neuronal glutamate signalling pathways

It is becoming increasingly apparent that the role of glutamate receptors in signalling at synapses is not confined to the CNS, as once believed, and that they also function in several non-neuronal tissues. The aim of this review is to summarise current knowledge regarding peripheral glutamate signalling and discuss the role of glutamate as a more ubiquitous signalling agent. As one avenue for therapeutic intervention may be by manipulation of intercellular communication pathways, increased awareness and understanding of glutamate signalling will help in the design of treatment schedules for a range of biological disorders including skin disease, osteoporosis, blood clotting disorders and diabetes. These avenues have the possibility to advance rapidly into clinical practice because agents developed to modulate central glutamate receptor function could be targeted to new sites without the requirement for completely new drug discovery or clinical chemistry programmes.     

Caroverine depresses the activity of cochlear glutamate receptors in guinea pigs: in vivo model for drug-induced neuroprotection?

With the aid of microiontophoretic techniques the action of caroverine, a quinoxaline-derivative, was tested on the receptor-linked depolarisation of the subsynaptic membrane of cochlear afferents. This membrane can be depolarised by the afferent transmitter agonist glutamate, mediated by NMDA and non-NMDA receptors and by acetylcholine, one of the different transmitter substances, released physiologically on axodendritic efferent synapses. Caroverine antagonized the membrane response to glutamate in an enduring but reversible manner. In contrast, the drug exhibited no effect on the depolarising action of acetylcholine. Therefore, the pharmacological profile of caroverine corresponded to the action of selective glutamate receptor antagonists. Since glutamate is likely to be the major mediator of neurotoxicity in the central nervous system, the selective glutamate-antagonism of caroverine is of particular interest, due to its putative neuroprotective competence. Caroverine is currently available clinically in some countries as a spasmolytic drug. Following these results it is proposed to test the drug for clinical efficacy in putatively glutamate-induced, excitotoxic disorders of the brain.     

Caroverine depresses the activity of cochlear glutamate receptors in guinea pigs: In vivo model for drug-induced neuroprotection?

With the aid of microiontophoretic techniques the action of caroverine, a quinoxaline-derivative, was tested on the receptor-linked depolarisation of the subsynaptic membrane of cochlear afferents. This membrane can be depolarised by the afferent transmitter agonist glutamate, mediated by NMDA and non-NMDA receptors and by acetylcholine, one of the different transmitter substances, released physiologically on axodendritic efferent synapses. Caroverine antagonized the membrane response to glutamate in an enduring but reversible manner. In contrast, the drug exhibited no effect on the depolarising action of acetylcholine. Therefore, the pharmacological profile of caroverine corresponded to the action of selective glutamate receptor antagonists. Since glutamate is likely to be the major mediator of neurotoxicity in the central nervous system, the selective glutamate-antagonism of caroverine is of particular interest, due to its putative neuroprotective competence. Caroverine is currently available clinically in some countries as a spasmolytic drug. Following these results it is proposed to test the drug for clinical efficacy in putatively glutamate-induced, excitotoxic disorders of the brain.     

Novel metabotropic glutamate receptor 4 and glutamate receptor 8 therapeutics for the treatment of anxiety

Introduction: The fast actions of the excitatory neurotransmitter glutamate are mediated by glutamate-gated ion channels (ionotropic Glu receptors). Metabotropic glutamate receptors (mGlus) are coupled to second messenger pathways via G proteins and modulate glutamatergic and GABAergic neurotransmission. Of the eight different types of mGlus (mGlu1–mGlu8), mGlu4, mGlu6, mGlu7 and mGlu8 are members of group III. Except for mGlu6, group III receptors are generally located presynaptically and regulate neurotransmitter release. Because of their role in modulating excitatory neurotransmission, mGlus are attractive targets for therapies aimed at treating anxiety disorders.

Areas covered: In this review, the authors discuss the role of mGlu4 and mGlu8 in anxiety disorders. They also discuss how mGlu4 and mGlu8 have distinct expression patterns in the brain, which might have related functions. Finally, the authors discuss how compounds that target more than one mGlu receptor might be therapeutically more effective.

Expert opinion: mGlu4 might compensate for mGlu8 deficiency, and deficiency of both receptors might result in a more pronounced phenotype than deficiency of either receptor alone. The distinct and overlapping anatomical distribution and functions of mGlu4 and mGlu8 suggest that both receptors, either individually or combined, are attractive therapeutic targets in anxiety disorders, post-traumatic stress disorder, Parkinson’s disease, and multiple sclerosis.     

GABA and glutamate systems as therapeutic targets in depression and mood disorders

Advances made in diverse areas of neuroscience suggest that neurotransmitter systems, additional to the monoaminergic, contribute to the pathophysiology of mood disorders. This ever accruing body of preclinical and clinical research is providing increased recognition of the contribution made by amino acid neurotransmitters to the neurobiology of mood disorders. This review examines evidence supporting the role of GABA and glutamate in these processes and explores the potential to target these systems in the development of novel compounds; the viability of these agents for treatment-related co-morbidities will also be considered.     

6-羟基多巴的细胞毒作用与谷氨酸转运的关系

目的探讨6-羟基多巴(6-OHDA)导致细胞毒性与谷氨酸(glutamate,Glu)递质水平和谷氨酸转运体的相关性。方法大鼠脑黑质内定位注射6-OHDA,制备帕金森病(Parkinson's disease,PD)动物模型;用在体微透析技术收集大鼠纹状体细胞外液;用高效液相色谱法测定PD大鼠纹状体和PC12细胞的细胞外液中Glu的水平;用流式细胞仪和酶标仪检测细胞凋亡率和细胞活性;通过测定L-［³H］-Glu的摄取能力确定谷氨酸转运体的功能。结果6-OHDA诱导PC12细胞和大鼠损毁侧纹状体释放Glu增加,使PC12细胞凋亡和活性降低,而PC12细胞和突触体上的谷氨酸转运体功能显著下降。结论6-OHDA引起的神经毒性与其增加Glu释放和降低谷氨酸转运体功能有关。     

代谢型谷氨酸受体与应激损伤

代谢型谷氨酸受体 (mGluRs)在应激性损伤中的作用日益受到重视 ,它可参与GC水平的调节 ,影响谷氨酸神经毒性作用和突触可塑性 (LTP、LTD)的诱导 ,由此表明mGluRs在应激性损伤中可能占有重要的地位。由于不同类型的mGluRs具有不同的作用 ,机制较为复杂 ,因此 ,今后还需进一步加强mGluRs与应激性损伤关系的研究     

Serum glutamate in rhesus macaques after gavage with MSG

Administration of monosodium glutamate (MSG) to rhesus monkeys caused a dose-related increase in serum glutamate concentration, and Na⁺ concentration is also increased when large quantities of MSG are ingested. Vomiting occurs in 50% of treated monkeys but is not precisely correlated with serum glutamate levels. The concentration of glutamate in vomitus reflects the dosage of MSG given. Monkeys with enteritis have high basal serum glutamate levels.