抑郁症受体机制研究进展

以往研究证实,抑郁症与单胺类受体有关,现阶段又发现了多种受体参与了抑郁症的病理生理过程。该文综述了谷氨酸受体、促肾上腺皮质激素释放激素受体、神经激肽受体、糖皮质激素受体在抑郁症发病机制中所起作用的研究进展。     

α1肾上腺素受体拮抗剂的研究进展

介绍α1肾上腺素受体拮抗剂的研究进展。α1肾上腺素受体亚型的研究进展,受体的分子生物学研究以及亚型分类的研究,随后介绍了α1肾上腺素受体拮抗剂的药理作用以及药理方面的新发展即在治疗男性良性前列腺增生中的应用。     

气道毒蕈碱受体亚型研究进展

随着毒蕈碱（Ｍ）受体异质性的确定及分子生物学基础的阐明，Ｍ受体亚型的功能及定量分布研究取得了一系列进展，本文介绍了气道Ｍ受体亚型的分布及其功能，为临床选择性用药提供指导。     

以5-羟色胺2A受体为靶点的抗抑郁药研究进展

抑郁症的发病机制非常复杂，至今尚未完全阐明。大量临床及临床前研究表明，5-羟色胺(5-HT)能神经功能障碍可能是导致抑郁症的关键因素之一。在5-HT神经系统中，除5-羟色胺转运体(SERT)外，有多种5-HT受体亚型与抑郁症有关，尤以5-HT_1A及5-HT_2A受体与抑郁症关系最为密切。5-HT_2A受体在大脑中广泛分布，是调节情绪的重要物质基础，对情绪、感知的调控具有重要作用。5-HT_2A受体可以直接或间接调节单胺类递质释放，调节脑中单胺类递质水平，参与抑郁症发病过程。5-HT_2A受体拮抗剂可以增强5-羟色胺再摄取抑制剂等抗抑郁药对难治性抑郁症的治疗效果并减少性功能障碍及睡眠障碍等不良反应。目前有不少以5-HT_2A受体为靶点的抗抑郁药应用于临床，也有大量化合物处于临床及临床前研究。该文对5-HT_2A受体与抑郁症的关系及以5-HT_2A受体为靶点的抗抑郁药研究进展进行简要综述，以期为新型抗抑郁药物的研发提供参考。     

速效抗抑郁药的作用靶点研究进展

抑郁症是一种慢性复发性精神疾病,传统抗抑郁药通常需要连续几周的治疗才能发挥显著的治疗效果。N-甲基-D-天冬氨酸受体拮抗剂氯胺酮的上市为速效抗抑郁药物的研发打开了一个全新的视角,胆碱能受体阻滞剂东莨菪碱、5-HT2A受体激动剂赛洛西宾也表现出快速抗抑郁的作用潜力。归纳了谷氨酸能速效抗抑郁药、胆碱能受体拮抗剂、5-HT2A受体激动剂（致幻剂）速效抗抑郁药的药理学靶点研究,分析了新靶点的可能策略,以期对未来抗抑郁药物研究方向有所启示。     

多巴胺受体及其与抑郁症的相关性研究进展

抑郁症是由多方面原因引起的以抑郁为主要症状的一组心境障碍或情感性障碍[1]。这种不愉快的心境体验严重影响人们的生活质量,具有高发病率、高自杀率、低治疗率等特点,尤其在女性及老年男性中较为高发[2-3]。虽然抑郁症表现复杂,病因、病理机制迄今尚未明确,但随着分子生物学的进展及神经递质假说和受体假说的提出,目前抑郁症在涉及5-羟色胺(5-HT)、去甲肾上腺素(NE)和多巴胺(DA)等单胺类递质系统的功能紊     

基于系统药理学逍遥散治疗抑郁症的分子机制初探

目的从分子角度揭示逍遥散治疗抑郁症的分子机制,初步揭示中药复方治疗的科学内涵。方法运用系统药理学理论和方法,对中药成分、靶点等生物数据进行挖掘,构建"药物-靶点-疾病"网络,并对配伍机制进行分析。结果柴胡通过作用于MAO受体和SLC6A受体,治疗抑郁症主要症状;当归、白芍通过靶点CYP系列酶、AKRS超家族、ADORA受体,主要作用于食欲不振、全身乏力等兼症;茯苓、白术、甘草主要作用于AKRS超家族、ADORA受体,生姜、薄荷则作用于靶点SLC6A受体,它们协同治疗失眠等临床表现;甘草调和药性,作为使药之用。结论通过系统药理学模型的构建,从分子层面系统阐释逍遥散中诸药分别作用于抑郁症及其临床症状的机制,体现出中药复方协同发挥治疗抑郁症的作用。为中药复方分子机制的阐明及其质量标记物的遴选提供研究思路及方法。     

雌激素受体与抑郁症的相关性研究进展

雌激素主要通过雌激素受体发挥抗抑郁作用。目前研究较多的是雌激素受体 α（ERα）、雌激素受体 β （ERβ）和 G蛋白偶联雌激素受体（GPER）。三者在雌激素的抗抑郁作用中发挥不同的效应,其中 GPER可能与雌激 素的快速抗抑郁作用有关。深入了解雌激素受体的不同效应对于寻找治疗抑郁症的新靶点,充分发挥雌激素的抗 抑郁作用,最大程度减少其不良反应具有重要意义。     

抑郁症相关受体作用机制的研究进展

抑郁症是一种病因很复杂的疾病,其发病机制与受体有着密切的关系。本文简要介绍了几种与抑郁症相关的受体,阐述了其生理功能及在抑郁症发病机制中的作用。     

线粒体能量代谢障碍在抑郁症发病机制中的关键作用

抑郁症是一种以心境障碍为主要临床特征的常见精神类疾病,严重危害人类健康。近年来,越来越多的研究表明抑郁症患者体内线粒体功能、结构等出现异常,而线粒体超微结构的变化可导致机体能量代谢障碍,遂提出线粒体能量代谢障碍可能是抑郁症的发病机制之一。本文从线粒体结构、功能、复合体和分子水平等方面综述了抑郁症的发病机制,为抑郁症的临床治疗及抗抑郁药物新靶点的发现提供依据。     

肠道菌群相关的抗抑郁治疗研究进展

目的 介绍肠道菌群与抑郁症的病理机制以及相关治疗的研究进展,为后续以肠道菌为靶点的抗抑郁药物的研发提供帮助。方法 查阅近年来肠道菌群与抑郁症方面的33篇中英文文献进行分类总结,从肠道菌群的门、科、属水平的角度探讨了抑郁状态下肠道菌群多样性的变化,从分子水平上阐述了肠道菌与抑郁症发病机制之间的关系,总结现有相关研究,进一步探索以肠道菌群为靶点进行药物研发治疗的可行性。结果 肠道菌紊乱与抑郁症之间相互作用,现有益生菌等生物制剂可通过改善肠道菌群病理状态下的紊乱对抑郁症治疗起到缓解作用。结论 肠道菌群失调与抑郁的发生密切相关,以肠道菌为靶点的相关药物研发治疗,可能成为治疗抑郁症的新途径。     

Depression and Alzheimer's disease: Neurobiological links and common pharmacological targets

Depression is one of the most prevalent and life-threatening forms of mental illnesses, whereas Alzheimer's disease is a neurodegenerative disorder that affects more than 37 million people worldwide. Recent evidence suggests a strong relationship between depression and Alzheimer's disease. A lifetime history of major depression has been considered as a risk factor for later development of Alzheimer's disease. The presence of depressive symptoms can affect the conversion of mild cognitive impairment into Alzheimer's disease. Neuritic plaques and neurofibrillary tangles, the two major hallmarks of Alzheimer's disease brain, are more pronounced in the brains of Alzheimer's disease patients with comorbid depression as compared with Alzheimer's disease patients without depression. On the other hand, neurodegenerative phenomena have been observed in different brain regions of patients with a history of depression. Recent evidence suggests that molecular mechanisms and cascades that underlie the pathogenesis of major depression, such as chronic inflammation and hyperactivation of hypothalamic-pituitary-adrenal (HPA) axis, are also involved in the pathogenesis of Alzheimer's disease. In particular, a specific impairment in the signaling of some neurotrophins such as transforming-growth-factor β1 (TGF-β1) and brain-derived neurotrophic factor (BDNF) has been observed both in depression and Alzheimer's disease. In the present review we will examine the evidence on the common molecular pathways between depression and Alzheimer's disease and we will discuss these pathways as new pharmacological targets for the treatment of both major depression and Alzheimer's disease.     

Review of Pharmacological Treatment in Mood Disorders and Future Directions for Drug Development

After a series of serendipitous discoveries of pharmacological treatments for mania and depression several decades ago, relatively little progress has been made for novel hypothesis-driven drug development in mood disorders. Multifactorial etiologies of, and lack of a full understanding of, the core neurobiology of these conditions clearly have contributed to these development challenges. There are, however, relatively novel targets that have raised opportunities for progress in the field, such as glutamate and cholinergic receptor modulators, circadian regulators, and enzyme inhibitors, for alternative treatment. This review will discuss these promising new treatments in mood disorders, the underlying mechanisms of action, and critical issues of their clinical application. For these new treatments to be successful in clinical practice, it is also important to design innovative clinical trials that identify the specific actions of new drugs, and, ideally, to develop biomarkers for monitoring individualized treatment response. It is predicted that future drug development will identify new agents targeting the molecular mechanisms involved in the pathophysiology of mood disorders.     

Depressed or demented: common CNS drug targets?!

A body of evidence emerging in antidepressant and antidementia research has revealed a convergence of molecular events known to regulate neuronal plasticity in learning and memory with molecular actions of drugs for the treatment of depression. Many antidepressants are reported to have positive impact on learning and memory. These include agents acting through monoaminergic neurotransmitter systems, non-monoaminergic transmitter systems, and hormones. On the other hand, agents that appear to have memory-enhancing or antidementia value are frequently found to exhibit antidepressant activity in patients and animal depression models. It is becoming clear that the comorbidity of depression and dementia does not occur by chance, but rather is an inevitable consequence of pathologic relationships between the conditions. Molecular mechanisms and cascades that underlie memory may be shared by mood regulation and are vulnerable to stress and injuries. This review focuses on recent findings regarding effects of a variety of agents on dementia and depression and their common molecular mechanisms as well as their differences. A better understanding of the key underlying molecular components whose changed activities have dramatic influences on mood and cognition may lead to the development of novel and more effective therapeutic agents for the treatment of depression and dementia. In this review, some of the recent findings that suggest novel therapeutic strategies are also highlighted.     

New strategies in the development of antidepressants: towards the modulation of neuroplasticity pathways

Over the past five decades, the pharmacological treatment of depression has been based on the pathophysiological hypothesis of a deficiency in monoamines, mainly serotonin and noradrenaline. Antidepressant prescribed today, all of them designed to enhance central monoaminergic tone, present several important limitations, including a 2-5 weeks response lag and also a limited clinical efficacy. As it is increasingly evident that the abnormalities associated to depression go beyond monoamines, the development of better antidepressants will depend on the identification and understanding of new cellular targets. In this regard, much evidence supports a role for cellular and molecular mechanisms of neuroplasticity, including neurotrophic inputs, in mood disorders, in parallel with the biological features associated to stress conditions. In order to illustrate the possible relevance of neuroplasticity-related pathways for the therapy of depressive states, we here review the biological evidence supporting some therapeutic strategies in a very initial phase of development (modulation of the Wnt/GSK-3β/β-catenin pathway, potentiation of endocannabinoid activity, agonism of 5-HT(4) receptors), which involve modulation of downstream mechanisms and neuroplasticity circuits. These strategies also show the existence of mixed mechanisms of action, constituting a nexus between the "classic" aminergic theory and the "new" neuroplasticity hypothesis.     

Dysfunction of brain neurovascular unit and depression北大核心CSCD

The neurovascular unit(NVU) is a dynamic functional module, which is composed of neurons, astrocytes, microglia and other components. The disturbance of NVU can cause some neurological and psychological diseases. Neuro-inflammation has been regarded as one of the causes of depression and associated with neurovascular dysfunction in recent years. The dysfunction of NVU is closely related to depression. It is important to investigate the interactions between NVU and depression. This review is intended to elaborate the role of NVU in development and formation of depression and the underlying neuro-inflammation molecular mechanisms, which will contribute to further studies.     

单胺转运蛋白与单胺重摄取抑制剂研究进展

5-羟色胺转运蛋白(serotonin transporter,SERT)和去甲肾上腺素转运蛋白(norepinephrine transporter,NET)是单胺类神经递质转运体,其功能是将释放到突触间隙的5-羟色胺(serotonin,5-HT)和去甲肾上腺素(norepinephrine,NE)分别转运入突触前神经细胞,以终止相应的突触信号传递。SERT、NET抑制剂可阻断5-HT和NE的重摄取,提高突触间隙单胺递质水平,从而发挥抗抑郁效应。SERT、NET作为主流抗抑郁药物的作用靶标,了解其分布与功能、分子结构和活性调节因素,以及单胺重摄取抑制剂的作用机制对抗抑郁药物研发及应用具有重要意义。     

Inactivation of 5HT transport in mice: modeling altered 5HT homeostasis implicated in emotional dysfunction, affective disorders, and somatic syndromes

Animal models have not only become an essential tool for investigating the neurobiological function of genes that are involved in the etiopathogenesis of human behavioral and psychiatric disorders but are also fundamental in the development novel therapeutic strategies. As an example, inactivation of the serotonin (5HT) transporter (5Htt, Slc6a4) gene in mice expanded our view of adaptive 5HT uptake regulation and maintenance of 5HT homeostasis in the developing human brain and molecular processes underlying anxiety-related traits, as well as affective spectrum disorders including depression. 5Htt-deficient mice have been employed as a model complementary to direct studies of genetically complex traits and disorders, with important findings in biochemical, morphological, behavioral, and pharmacological areas. Based on growing evidence for a critical role of the 5HTT in the integration of synaptic connections in the rodent, nonhuman primate, and human brain during critical periods of development and adult life, more in-depth knowledge of the molecular mechanisms implicated in these fine-tuning processes is currently evolving. Moreover, demonstration of a joint influence of the 5HTT variation and environmental sources during early brain development advanced our understanding of the mechanism of genexgene and genexenvironment interactions in the developmental neurobiology of anxiety and depression. Lastly, imaging techniques, which become increasingly elaborate in displaying the genomic influence on brain system activation in response to environmental cues, have provided the means to bridge the gap between small effects of 5HTT variation and complex behavior, as well as psychopathological dimensions. The combination of elaborate genetic, epigenetic, imaging, and behavioral analyses will continue to generate new insight into 5HTT's role as a master control gene of emotion regulation.     

Dual effects of bryostatin-1 on spatial memory and depression

Dementia and depression are clinical symptoms commonly associated in patients. Emerging evidence suggests that the two diseases share many profiles in their development and underlying neural/molecular mechanisms. Thus, interest is raised in developing new classes of antidepressant agents with activity of cognitive enhancement. Here, we show that bryostatin-1, a protein kinase C substrate activator, at bilateral intracerebroventricular doses of 0.64 or 2 pmol/site, significantly enhanced learning and memory of rats in a spatial water maze task. When applied at the doses at which it exhibits memory-enhancing activity, bryostatin-1 showed a significant antidepressant activity, as determined in an open space swim test. Both effects were not observed when a smaller dose was administered and were largely eliminated by co-administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), a protein kinase C inhibitor. These results support the hypothesis that memory processing and mood regulation share common neural mechanisms. Restoring impaired mood regulation with antidepressant agents that also exhibit memory-enhancing activity may represent one of the new strategies in the fight against depression associated with memory impairments.     

The CRF peptide family and their receptors: yet more partners discovered

Abnormal signaling at corticotropin-releasing factor CRF1 and CRF2 receptors might contribute to the pathophysiology of stress-related disorders such as anxiety, depression and eating disorders, in addition to cardiac and inflammatory disorders. Recently, molecular characterization of CRF1 and CRF2 receptors and the cloning of novel ligands--urocortin, stresscopin-related peptide/urocortin II, and stresscopin/urocortin III--have revealed a far-reaching physiological importance for the family of CRF peptides. Although the physiological roles of the CRF2 receptor remain to be defined, the preclinical and clinical development of specific small-molecule antagonists of the CRF1 receptor opens new avenues for the treatment of psychiatric and neurological disorders.