N-甲基-D-天冬氨酸受体与抑郁障碍

越来越多研究表明,除单胺神经递质外,谷氨酸及相关受体在抑郁症病因中也扮演了重要的角色,特别是N-甲基-D-天冬氨酸(NMDA)受体,有证据表明NMDA受体的过度激活是抑郁障碍的病理生理机制之一。本文总结了谷氨酸及相关受体与抑郁障碍的关系,对NMDA受体成为潜在抗抑郁药靶点做一简要讨论。     

抗N-甲基-D-天冬氨酸受体脑炎

抗N-甲基-D-天冬氨酸受体(anti-N-methyl-D-aspartate receptor,NMDAR)脑炎是与NMDAR的亚单位NR1相关的一种脑炎,其特点为病程呈多阶段性,主要表现为精神异常、记忆障碍、癫痫发作、意识水平降低等,常伴有运动障碍、自主神经功能紊乱和呼吸节律异常。     

记忆网络中的N-甲基-D-天冬氨酸受体

N-甲基-D-天冬氨酸(NMDA)受体属谷氨酸离子型受体,其与突触的可塑性和学习记忆密切相关。中枢神经系统中与学习记忆相关的,如以胆碱受体、谷氨酸受体、腺苷A1受体等为代表的诸多受体及递质,以谷氨酸(Glu)/GABA为代表的氨基酸能神经通路,以长时程增强(LTP)等为代表的脑内神经电活动,以脑源性神经营养因子(BDNF)等为代表的基因蛋白遗传信息改变,甚至许多神经退行性疾病中Glu的神经毒性,等等,都与NMDA受体相关,通过NMDA受体功能的改变调控学习记忆功能,进而对整个中枢神经系统产生影响。换句话说,如果把学习记忆的信息传递系统看做一个庞大的信息网络,那么NMDA受体就是学习记忆相关神经网络中一个相对中心的关键位点。因此,以探讨NMDA受体在学习记忆错综复杂网络中的关联为切入点,以微观深入研究为基础、以宏观视野分析为引领,全方位评价NMDA受体在学习记忆网络中的作用,或许可以引领未来脑功能及相关疾病系统的研究。     

儿童抗N-甲基-D-天冬氨酸受体脑炎19例临床分析

目的:总结儿童抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎临床特点,以提高临床医师对该病的认识。方法:回顾性分析2015年12月至2017年3月于江西省儿童医院神经内科就诊的19例抗NMDAR脑炎患儿的临床表现、辅助检查、治疗、预后。结果:临床主要表现为精神行为异常、抽搐、运动障碍、睡眠障碍;10例头颅MRI异常;17例脑电图异常,主要表现为背景活动慢;5例脑脊液常规异常,淋巴细胞增高为主;2例血清抗NMDAR抗体IgG阴性,17例血清抗NMDAR抗体阳性及19例脑脊液抗体阳性;17例予一线免疫治疗,15例好转;随访16例,15例均好转,其中2例复发。结论:儿童抗NMDAR脑炎无明显性别差异,临床主要表现为精神异常、抽搐、运动障碍、睡眠障碍,出现中枢性通气障碍及合并肿瘤较少见,约半数头颅MRI表现异常,主要为颞叶受损;脑电图主要表现为背景活动慢,脑脊液无明显特异改变,少部分血清免疫抗体可为阴性;多数一线免疫治疗有效,大部分预后良好,复发率低于成人。     

N-甲基-D-天冬氨酸受体与全身麻醉药对发育期大脑的神经毒性

N-甲基-D-天冬氨酸(NMDA)受体是一类对Ca2+高度通透性配体门控离子通道。NMDA受体在脑发育突触可塑性、学习记忆方面都起到重要作用,也是全身麻醉药作用的主要靶点之一。全身麻醉药诱导发育期大脑神经毒性,进而影响成年期认知功能发育,这是否由NMDA受体介导,尚待进一步研究予以证实。     

N-甲基-D-天冬氨酸受体拮抗剂类药物在脑缺血损伤中的应用进展

综述了近年来N-甲基-D-天冬氨酸受体拮抗剂治疗脑缺血的应用进展，并从不同作用位点分别对各类药物特点作了阐述。     

利妥昔单抗治疗抗N-甲基-D-天冬氨酸受体脑炎的研究进展

抗N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor, NMDAR)脑炎是一种较为常见的免疫介导性脑炎,好发于18岁以下儿童。抗NMDAR脑炎可表现为进行性精神病、癫痫及自主功能障碍,若不加干预和治疗则易导致患者死亡。利妥昔单抗常用于抗NMDAR脑炎的二线免疫治疗,临床效果较为显著。本文就利妥昔单抗治疗抗NMDAR脑炎的研究进展做一综述。     

米诺环素对大鼠皮质神经元的毒性及N-甲基-D-天冬氨酸损伤的保护作用

目的　更全面地了解米诺环素对中枢神经系统的作用。方法　神经元与不同浓度米诺环素和(或 )N 甲基 D 天冬氨酸 (NMDA)作不同时间处理后 ,观察细胞形态 ,并以MTT试验评价细胞活性。结果　米诺环素 135 μmol·L- 1处理 2 4h明显降低体外培养 4 ,7,10d神经元的活性 (P <0 .0 1) ,13.5μmol·L- 1以下则无明显影响 ;4 5 ,135 μmol·L- 1米诺环素处理 3h对体外培养 10d神经元活性没有影响 ,处理 2 4h则活性明显下降 (P <0 .0 1)。米诺环素 4 5 ,135 μmol·L- 1可保护 5 0 μmol·L- 1NMDA损伤3h后的神经元活性 ,但对 15 μmol·L- 1NMDA损伤2 4h后无效 ;15 μmol·L- 1米诺环素则仅对 15 μmol·L- 1NMDA损伤 2 4h后有效。结论　米诺环素对大鼠原代皮质神经元有双重作用 ,高浓度长时间处理有毒性作用 ,但高浓度能保护神经元NMDA急性损伤 ,低浓度能保护延缓性损伤     

抗N-甲基-D-天冬氨酸受体脑炎合并多处感染患者的药学监护

目的:探讨临床药师对抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎合并多处感染患者开展药学监护的方法。方法:以1例临床病例为切入点,分析临床药师在抗NMDAR脑炎合并多处感染治疗方案中的药学监护点,从抗菌药物的选择、药动学角度建议给药方法,对药品不良反应处理、营养支持等方面提出建议。结果:通过实施药学监护,临床药师及时解决了患者肝功能异常等不良反应,患者症状逐渐好转直至出院。结论:临床药师通过对患者的药学监护,排查用药安全隐患,避免严重不良反应的发生。     

N-甲基-D-天冬氨酸受体相关性骨癌痛作用机制研究进展

目的 探讨N-甲基-D-天冬氨酸(NMDA)受体相关性骨癌痛的作用机制。方法 检索国内外相关文献,从NMDA受体及其亚基NR1和NR2B,以及NMDA相关性通路方面进行总结与分析。结果 作用机制包括驱动蛋白家族KIF17介导的NR2B树突转运,炎性因子诱导NMDA受体亚基磷酸化,以及含NR2B的NMDA受体-Ca²⁺/Ca²⁺-钙调蛋白依赖性蛋白激酶Ⅱ(CaMKⅡ)-环磷酰腺苷反应元件结合蛋白(CREB)-CREB转录共激活因子1(CRTC1)-脑源性神经营养因子(BDNF)-NR2B的正反馈通路。结论 相关研究可为骨癌痛的镇痛治疗提供新的参考靶点,同时也为临床骨癌痛的镇痛治疗提供了参考。     

Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity.

The NMDA receptor has been widely investigated in recent years as a target for the pharmacological management of seizures, pain and a variety of neurological disorders. Its role in normal central nervous system (CNS) activity and development, as well as in the development of CNS abnormalities and neurodegeneration has also been of interest. The NMDA receptor is one of three pharmacologically distinct subtypes of ionotropic receptor channels that are sensitive to the endogenous excitatory amino acid, L-glutamate. The ontogeny of the NMDA receptor, a multiple tetrameric and heteromeric channel complex with at least six known subunits, is controlled by three gene families and varies in developmental profile with species and regional brain area. NMDA receptors play a role in excitatory synaptic transmission, in the activity-dependent synaptic plasticity underlying learning and memory, and in pre- and postnatal CNS development, including brain cell differentiation, axonal growth and degeneration of unused neurons. The results of recent studies suggest that sustained alteration of NMDA receptor activation during critical periods of development may have deleterious effects on normal CNS development and function. Neonatal rats administered the NMDA receptor antagonists 2-amino-5-phosphonovalerate (AP5) and MK-801 during the first two weeks of life develop abnormal axonal arborization in the retinal connections to the superior colliculus, interfering with normal visual responses. Results from monkey studies suggest that chronic developmental exposure to high doses of a NMDA antagonist, remacemide, has pronounced and long-lasting effects on learning. Recent findings indicate that if NMDA receptors are blocked during a specific period in neonatal life (first two weeks postnatally in the rat), massive apoptotic neurodegeneration results, due not to excitotoxic overstimulation of neurons but to deprivation of stimulation. These observations require further laboratory evidence and support in order to establish their relevance to drug-induced human neurodevelopmental concerns. It is necessary to investigate the relevance of these findings in other animal species in addition to the rat, most notably, nonhuman primates, where neuronal cytoarchitecture and development are significantly different than the rodent but more like the human.     

Enhancement of NMDA responses by group I metabotropic glutamate receptor activation in striatal neurones

1. The interactions between N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors (mGluRs) were investigated in striatal slices, by utilizing intracellular recordings, both in current- and voltage-clamp mode.
2. Bath-application (50 μM) or focal application of NMDA induced a transient membrane depolarization, while in the voltage-clamp mode, NMDA (50 μM) caused a transient inward current. Following bath-application of the non-selective mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, 10 μM), NMDA responses were reversibly potentiated both in current (197±15% of control) and voltage-clamp experiments (200±18% of control).
3. Bath-application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG, 10–300 μM) resulted in a dose-dependent potentiation of NMDA-induced membrane depolarization (up to 400±33% of control). This potentiation was either prevented by preincubation with (RS)-α-methyl-4-carboxyphenylglycine (RS-α-MCPG, 300 μM), or blocked when applied immediately after 3,5-DHPG wash-out.
4. Neither (2S,1′S,2′S)2-(2′-carboxycyclopropyl)glycine (L-CCG I, up to 100 μM) nor (2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)-glycine (DCG-IV, 1 μM), agonists for group II mGluRs caused any change in NMDA responses. Likewise, L-serine-O-phosphate (L-SOP, 30 μM), agonist for group III mGluRs, did not affect the NMDA-induced depolarization.
5. The enhancement of the NMDA responses was mimicked by phorbol-12,13-diacetate (PDAc, 1 μM) which activates protein kinase C (PKC). The 3,5-DHPG-mediated potentiation of the NMDA-induced depolarization was prevented by preincubation with staurosporine (100 nM) or calphostin C (1 μM), antagonists of PKC.
6. Electrophysiological responses to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor activation were not affected by agonists for the three-classes of mGluRs.
7. The present data suggest that group I mGluRs exert a positive modulatory action on NMDA responses, probably through activation of PKC. This functional interaction in the striatum appears of crucial importance in the understanding of physiological and pathological events, such as synaptic plasticity and neuronal death, respectively.

     

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。     

Modification of the N-methyl-D-aspartate response by antidepressant σ receptor ligands

Sertraline, a selective serotonin reuptake inhibitor, and clorgyline, a monoamine oxidase inhibitor, both of which have high affinity for σ receptors, were assessed in an electrophysiological model. In keeping with previous data obtained with other σ receptor ligands, low doses of sertraline and of clorgyline potentiated selectively with a bell-shaped dose-response curve the effect of N-methyl-D-aspartate (NMDA) on pyramidal neurons in the CA₃ region of the rat dorsal hippocampus. This potentiation was reversed by the σ receptor ligands haloperidol and BMY-14802. The selective serotonin reuptake inhibitor paroxetine and the monoamine oxidase inhibitor tranylcypromine, both devoid of affinity for σ receptors, had no effects on the NMDA response. These data suggest that the effects of sertraline and clorgyline on the NMDA response are due to their affinity for σ receptors.     

Ketamine-induced neurotoxicity and changes in gene expression in the developing rat brain

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used for analgesia and anesthesia in obstetric and pediatric practice. Recent reports indicate that ketamine causes neuronal cell death in developing rodents and nonhuman primates. The present study assessed the potential dose- and time-dependent neurotoxic effects and associated changes in gene expression after ketamine administration to postnatal day 7 (PND-7) rat pups. Pups were exposed to ketamine subcutaneously at doses of 5, 10, or 20 mg/kg, in one, three or six injections respectively. Control animals received the same volume of saline at the same time points. The animals were sacrificed 6 h after the last ketamine or saline administration and brain tissues were collected for RNA isolation and histochemical examination. Six injections of 20 mg/kg ketamine significantly increased neuronal cell death in frontal cortex, while lower doses and fewer injections did not show significant effects. The ketamine induced cell death seemed to be apoptotic in nature. In situ hybridization demonstrated that NMDA receptor NR1 subunit expression was dramatically increased in the frontal cortex of ketamine treated rats. Microarray analysis revealed altered expression of apoptotic relevant genes and increased NMDA receptor gene expression in brains from ketamine treated animals. Quantitative RT-PCR confirmed the microarray results. These data suggest that repeated exposures to high doses of ketamine can cause compensatory up-regulation of NMDA receptors and subsequently trigger apoptosis in developing neurons.     

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。     

σ Receptor antagonist attenuation of methamphetamine-induced neurotoxicity is correlated to body temperature modulation

BackgroundMethamphetamine (METH) causes hyperthermia and dopaminergic neurotoxicity in the rodent striatum. METH interacts with σ receptors and σ receptor antagonists normally mitigate METH-induced hyperthermia and dopaminergic neurotoxicity. The present study was undertaken because in two experiments, pretreatment with σ receptor antagonists failed to attenuate METHinduced hyperthermia in mice. This allowed us to determine whether the ability of σ receptor antagonists (AZ66 and AC927) to mitigate METH-induced neurotoxicity depends upon their ability to modulate METH-induced hyperthermia.MethodsMice were treated using a repeated dosing paradigm and body temperatures recorded. Striatal dopamine was measured one week post-treatment.ResultsThe data indicate that the ability of σ receptor antagonists to attenuate METH-induced dopaminergic neurotoxicity is linked to their ability to block METH-induced hyperthermia.ConclusionThe ability of σ receptor antagonists to mitigate METH-induced hyperthermia may contribute to its neuroprotective actions.     

New trends in the development of AMPA receptor antagonists

The interest in AMPA glutamate receptors has grown enormously in recent years, due to their crucial role in physiological and pathological processes. This led to the development of AMPA ligands as research tools and potential therapeutic agents. In particular, extensive work was addressed towards the development of selective antagonists, which proved to be particularly useful in the prevention and treatment of a variety of neurological and non-neurological diseases. This review focuses on the primary and patent literature from 2000 onwards.