卒中后抑郁新的病因假说——谷氨酸能障碍

卒中后抑郁（post-stroke depression,PSD）是卒中后常见的神经精神症状之一,以心境低落、 兴趣下降为主要特征,不仅影响患者神经功能的康复,而且显著增加卒中病死率。其发病机制尚未 明确,伴随离子型谷氨酸受体拮抗剂氯胺酮的快速抗抑郁作用的出现,谷氨酸（glutamate,Glu）能神 经系统在抑郁症及PSD中的作用日益突出,也为抗抑郁治疗带来新的契机。     

谷氨酸能和γ氨基丁酸能系统与情感障碍

越来越多证据表明,谷氨酸能和γ氨基丁酸能(GABA)系统可能参与了抑郁症的发病过程.如抗抑郁药可直接或间接降低谷氨酸NMDA受体的功能;NMDA受体拮抗剂具有抗抑郁作用;降低谷氨酸能活性或抑制谷氨酸受体相关信号转导的药物具有抗躁狂作用.磁共振波谱的研究提示单相抑郁与皮质GABA浓度的减少有关;抗抑郁药和情绪稳定剂可提高皮质的GABA浓度,并改善情感障碍病人GABA缺乏的状况.因此研制作用于特异的谷氨酸受体和GABA受体的药物可能是未来抗抑郁药研究的热点.     

谷氨酸能和γ氨基丁酸能系统与情感障碍

越来越多语气表明，谷氨酸能和γ氨基丁酸能（GABA）系统可能能与了抑郁症的发病过程。如抗抑郁药可直接或间接降低谷氨酸NMDA受体的功能；NMDA受体拮抗剂具有抗抑郁作用；降低谷氨酸能活性或抑制谷氨酸受体相关信号转导的药物具有抗躁狂作用。磁共振波谱的研究提示单相抑郁与皮质GABA浓度的减少有关；抗抑郁药和情绪稳定剂可提高皮质的GANA浓度，并改善情感障碍病人GABA缺乏的状况。因此研制作用于特异的谷氨酸受体和GABA受体的药物可能是未来抗抑郁药研究的热点。     

抑郁障碍与谷氨酸功能

抑郁障碍是一种常见的慢性精神障碍。传统对抑郁障碍病因的解释主要集中在单胺类神经递质的功能失调上。近年来，越来越多的证据表明谷氨酸在抑郁障碍的发病机制中充当着重要的作用。本文将围绕谷氨酸及其受体的功能，以及谷氨酸功能失调在抑郁障碍动物模型与临床初步研究等作一概述。     

谷氨酸能系统障碍与卒中后抑郁

近年来,大量研究表明谷氨酸能系统障碍可能与卒中后抑郁（PSD）的发病机制密切相关。本文主要从外周血小板功能障碍、海马神经元再生及重塑障碍两方面阐述谷氨酸能系统障碍在PSD病理生理机制中发挥的作用。     

急性缺血性卒中患者谷氨酸的释放研究

目的谷氨酸释放所致神经元兴奋毒性损伤在局灶性脑缺血的发病展性缺血性卒中患者谷氨酸升高的时间和谷氨酸释放抑制剂及谷氨酸受体拮抗剂的治疗时间窗.方法本研究共纳入128例脑梗死病人.用高效液相色谱分析(HPLC)检测了病人和对照者的血浆和脑脊液(CSF)谷氨酸浓度,并同时评定了加拿大卒中标准(CSS)积分和脑梗死容积(CTV).结果病人的平均血浆和CSF谷氨酸浓度均显著高于对照组(P分别小于0.01和0.001).50例进展性卒中患者的平均血浆和CSF谷氨酸浓度均显著高于78例稳定性卒中组.CTV≥10cm3的卒中患者的CSF谷氨酸浓度显著高于CTV＜10 cm3患者,并且50例进展性卒中患者的CSF谷氨酸浓度与其CTV值显著相关(r=0.303,P＜0.05).结论本结果提示,急性脑缺血患者预防神经病学进展,谷氨酸拮抗剂的应用有较宽的治疗时间窗.CSF中的谷氨酸含量可作为判断缺血性卒中的进展和谷氨酸释放抑制剂的一个指标.     

神经内科患者伴发抑郁状况与用药情况的横断面调查

目的 调查综合医院神经内科患者伴发抑郁症状的发病及诊疗情况。方法 2010年4月28日至5月21日期间30家综合医院神经内科的1281名患者连续入选参与调研。采用医院焦虑抑郁量表（Hospital Anxiety and Depression Scale,HAD）进行筛查。结果 神经内科患者中,44.0%（564/1281）为卒中患者,其既往使用抗抑郁药的比例为6.7%（38/564）;非卒中患者中,既往使用抗抑郁药的比例为17.4%（125/717）;入院后,卒中患者伴发抑郁的比例为50.0%（282/564）,非卒中患者伴发抑郁的比例为47.7%（342/717）;用药的构成比中,舍曲林用药率最高。结论 神经内科患者伴发抑郁的比例较高,尤其是卒中患者,但识别率和治疗率都很低,应该引起高度重视。     

代谢型谷氨酸受体与癫痫

代谢型谷氨酸受体是一类与G-蛋白偶联的调节离子通道和第二信使生成酶的特异受体,随着不同亚型的相继克隆以及功能的逐步阐明,其与神经系统疾病的关系引起了研究者的广泛兴趣。本文对代谢型谷氨酸受体各亚型在癫痫发作中的作用及其机制作一综述。     

Kainate受体与癫痫的研究进展

Kainate(KA)受体属于离子型谷氨酸受体(iGluRs)的一类亚型受体,与其它两种iGluRs,NMDA受体(N-甲基-D-门冬氨酸)和AMPA受体(氨基-3-羟基-5甲基-4-异恶丙酸)相比,具有其自身的生物学特性.近几年随着对KA受体研究的深入,发现KA受体与癫痫病的发病机制有一定的内在联系,因此对KA受体与癫痫关系的研究,可能为癫痫的临床治疗及新药研发开辟一条新的途径.本文介绍KA受体近年来的药理学特性、生理学功能及其在癫痫发病过程中的作用机制的研究进展.     

专题综述：卒中后抑郁

正编者按卒中是导致死亡的第三大病因,也是导致成年人长期残疾的主要原因,并有年轻化的趋势。抑郁是卒中患者较常见的神经精神症状之一,约有1/3以上的卒中患者在不同阶段罹患卒中后抑郁(post-stroke depression,PSD)。然而到目前为止,PSD的发病机制、诊断分类和诊断标准、卒中患者是否需要预防性使用抗抑郁药均没有明确的定论,因此本刊编辑部邀请张志教授等对上述问题作一评述,希望对大家有所启发。关于PSD的发病机制,早期提出的"卒中部位决定论"与"心理应激决定论"现在     

The role of glutamate receptors in traumatic brain injury: implications for postsynaptic density in pathophysiology

Traumatic brain injury (TBI) is the major cause of death and disability, and the incidence of TBI continues to increase rapidly. In recent years, increasing attention has been paid to an important structure at the postsynaptic membrane: the postsynaptic density (PSD). Glutamate receptors, as major components of the PSD, are highly responsive to alterations in the glutamate concentration at excitatory synapses and activate intracellular signal transduction via calcium and other second messengers following TBI. PSD scaffold proteins (PSD-95, Homer, and Shank), which anchor glutamate receptors and form a network structure, also have potential effects on these downstream signaling pathways. The changes in the function and structure of these major PSD proteins are also induced by TBI, indicating that there is a more complicated mechanism associated with PSD proteins in the pathophysiological process of TBI.     

Research into the specificity of depression after stroke: a review on an unresolved issue

Iwo decades of research have failed to generate consistent insight into the specificity of poststroke depression (PSD). This is, at least in part, caused by methodological difficulties. Differences in symptom profile between PSD and depression with no or another medical cause were described, but no specific and unequivocal clinical picture has been established so far. Prevalence rates of PSD varied largely between studies. In community based studies using standardised diagnostic instruments for depression, relatively low prevalence rates were reported compared to inpatient or rehabilitation studies. PSD occurs most frequently in the first few months after stroke, while a new incidence peak may occur 2-3 years after stroke. Two systematic reviews on the relation between lesion location and depression did not support the claim that left hemisphere lesions are a risk factor for PSD. A new concept of vascular depression has been proposed, which relates depression in the elderly to acute or chronic damage to the cerebral vascular system. Future efforts should aim at increasing the uniformity of study designs, assessment tools should be further improved for use in cognitively impaired patients and appropriate control groups should be defined to study the characteristic features of PSD.     

The role of glutamate on the action of antidepressants

Major depressive disorder (MDD) is a common, chronic, recurrent mental illness that affects millions of individuals worldwide. Currently available antidepressants are known to affect the monoaminergic (e.g., serotonin, norepinephrine, and dopamine) systems in the brain. Accumulating evidence suggests that the glutamatergic neurotransmission via the excitatory amino acid glutamate also plays an important role in the neurobiology and treatment of this disease. Clinical studies have demonstrated that the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant patients with MDD, suggesting the role of glutamate in the pathophysiology of treatment-resistant MDD. Furthermore, a number of preclinical studies demonstrated that the agents which act at glutamate receptors such as NMDA receptors, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and metabotropic glutamate receptors (mGluRs) might have antidepressant-like activities in animal models of depression. In this article, the author reviews the role of glutamate in the neuron-glia communication induced by potential antidepressants.     

AMPA receptors in the therapeutic management of depression

There is an increasing body of evidence implicating a role for alpha-amino-3-hydroxy-5-methyl-4 isoxazoleproprionic acid (AMPA) receptors in major depression and in the actions of antidepressant drugs. Alterations in AMPA receptors and other ionotropic glutamate receptors have been reported in depression, and following antidepressant treatment. Compounds which augment signaling through AMPA receptors (AMPA receptor potentiators) exhibit antidepressant-like behavioral effects in animal models, and produce neuronal effects similar to those produced by currently available antidepressants, including neurotrophin induction and increases in hippocampal progenitor cell proliferation. Additionally, the antidepressant fluoxetine has been found to alter AMPA receptor phosphorylation in a manner that is expected to increase AMPA receptor signaling. Data from mutant mice suggest that AMPA receptors may regulate the expression of brain-derived neurotrophic factor, a neurotrophin which has been implicated in the actions of antidepressant therapies. Combined, these data suggest that AMPA receptors may be in a key position to regulate mood disorders, and that compounds which target AMPA receptors may prove useful in the clinical management of depression.     

卒中后抑郁与脑小血管病关系的研究进展

卒中后抑郁为卒中常见并发症之一,不仅影响患者的精神及神经功能恢复,甚至增加患者的病死率、致残率,对患者的预后产生消极影响。卒中后抑郁与病变部位、病变程度等存在一定程度的相关性,但近年来研究证实脑小血管病变同样与卒中后抑郁的发生密切相关,随着人口老龄化的加剧,脑小血管病的发病率随之增加,它不仅是卒中后抑郁发生的危险因素,并且会加重卒中后抑郁的严重程度。本文对脑小血管病与卒中后抑郁的关系做一综述。     

Ontogeny of postsynaptic density proteins at glutamatergic synapses

In glutamatergic synapses, glutamate receptors (GluRs) associate with many other proteins involved in scaffolding and signal transduction. The ontogeny of these postsynaptic density (PSD) proteins involves changes in their composition during development, paralleling changes in GluR type and function. In the CA1 region of the hippocampus, at postnatal day 2 (P2), many synapses already have a distinct PSD. We used immunoblot analysis, subcellular fractionation, and quantitative immunogold electron microscopy to examine the distribution of PSD proteins during development of the hippocampus. Synapses at P2 contained substantial levels of NR1 and NR2B and most GluR-associated proteins, including SAP102, SynGAP, the chain of proteins from GluRs/SAP102 through GKAP/Shank/Homer and metabotropic glutamate receptors, and the adhesion factors, cadherin, catenin, neuroligin, and Nr-CAM. Development was marked by substantial decreases in NR2B and SAP102 and increases in NR2A, PSD-95, AMPA receptors, and CaMKII. Other components showed more moderate changes.     

Determinants and consequences of post-stroke depression.

Post-stroke depression (PSD) is a very frequent and important consequence of stroke, but, in spite of the high number of papers aiming to clarify various aspects of this disorder, controversies about its incidence, its (biological or psychological) determinants, its consequences and its treatment still persist. In the present survey we have taken separately into account each of these issues, starting from a critical discussion of the main factors which can affect the estimates of the incidence of PSD. We have then surveyed and updated the debate between proponents of a neuroanatomical and a psychological interpretation of PSD. Our conclusions have been that the most recent evidence does not support Robinson's influential neuroanatomical model, assuming that a left frontal stroke could provoke a major PSD, indistinguishable from the functional forms of major depression. In the section devoted to the consequences of PSD, we have particularly taken into account the problem of the deleterious influence that PSD could have on functional recovery. The available evidence does not allow us to conclude if an improvement of PSD also leads to an improvement of the patient's functional status. As for the therapy of PSD, a pharmacological treatment with selective serotonin reuptake inhibitors has proven effective and safe, whereas psychological methods of treatment of patients and their families have not yet given conclusive results.     

5-HTTLPR与卒中后抑郁及单相抑郁病因和疗效的关联分析

目的 探讨我国汉族人群卒中后抑郁（post-stroke depression,PSD）及单相抑郁（unipolar depression,UD）患者病因和疗效与5-羟色胺转运蛋白启动子区基因多态性（serotonin transporter gene-linked polymorphic,5-HTTLPR）之间的关系。方法 以4 5例P S D及41例U D患者作为研究对象,以149名正常人作对照,应用聚合酶链式反应（polymerase chain reaction,PCR）扩增技术测定所有研究对象的5-HTTLPR的基因型和等位基因,PSD和UD患者组患者使用氟西汀治疗12周,在基线及12周治疗末时使用汉密尔顿抑郁量表（Hamilton depressive scale,HAMD）-17项评定疾病严重程度及疗效。结果 5-HTTLPR的3种基因型（S/S、S/L和L/L）和等位基因（S和L）在PSD组、UD组和正常对照组之间的分布差异无统计学意义;PSD和UD组S/S纯合子与S/L杂合子及L/L纯合子的基线评分相比差异具有统计学意义;12周治疗后两组患者治愈组和未治愈组之间S/S与S/L和L/L基因型、S和L等位基因分布具有统计学差异。结论 5-HTTLPR与PSD及UD均无显著关联,S/S基因型患者可能抑郁症状较重,12周治疗后携带S/S基因型和S等位基因患者的临床痊愈率较低。     

The Notch ligand E3 ligase,Mind Bomb1, regulates glutamate receptor localization in Drosophila

The postsynaptic density (PSD) is a protein-rich network important for the localization of postsynaptic glutamate receptors (GluRs) and for signaling downstream of these receptors. Although hundreds of PSD proteins have been identified, many are functionally uncharacterized. We conducted a reverse genetic screen for mutations that affected GluR localization using Drosophila genes that encode homologs of mammalian PSD proteins. 42.8% of the mutants analyzed exhibited a significant change in GluR localization at the third instar larval neuromuscular junction (NMJ), a model synapse that expresses homologs of AMPA receptors. We identified the E3 ubiquitin ligase, Mib1, which promotes Notch signaling, as a regulator of synaptic GluR localization. Mib1 positively regulates the localization of the GluR subunits GluRIIA, GluRIIB, and GluRIIC. Mutations in mib1 and ubiquitous expression of Mib1 that lacks its ubiquitin ligase activity result in the loss of synaptic GluRIIA-containing receptors. In contrast, overexpression of Mib1 in all tissues increases postsynaptic levels of GluRIIA. Cellular levels of Mib1 are also important for the structure of the presynaptic motor neuron. While deficient Mib1 signaling leads to overgrowth of the NMJ, ubiquitous overexpression of Mib1 results in a reduction in the number of presynaptic motor neuron boutons and branches. These synaptic changes may be secondary to attenuated glutamate release from the presynaptic motor neuron in mib1 mutants as mib1 mutants exhibit significant reductions in the vesicle-associated protein cysteine string protein and in the frequency of spontaneous neurotransmission.