D-Serine: Basic Aspects with a Focus on Psychosis

D-Serine: Basic Aspects with a Focus on Psychosis
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D-丝氨酸:以精神病为重点的基本方面

DOI:
10.1007/978-3-319-56015-1_470-1
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发表时间:
2021
期刊:
NeuroPsychopharmacotherapy
影响因子:
--
通讯作者:
Masakazu Umino
Masakazu Umino
中科院分区:
--
文献类型:
--
作者:
Toru Nishikawa;Asami Umino;Masakazu Umino

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基于精神分裂症的谷氨酸假说,假设由GluN1和GluN2亚基组成的n -甲基- d -天冬氨酸型谷氨酸受体(NMDA受体)功能低下,d -丝氨酸被选为一种候选药物,有望通过恢复NMDA受体障碍,作为其拮抗剂之一,改善精神分裂症抗精神病阴性和认知症状。虽然d -丝氨酸尚未被批准用于临床,但对目前可用的抗精神病药物给予精神分裂症患者d -丝氨酸的随机对照试验的荟萃分析一致显示其阴性症状评分显著降低。本章首先验证NMDA受体介导的传递减少参与精神分裂症病理生理的证据,积累的数据说明了从功能减退到阳性、阴性和认知症状的合理机制,以及NMDA功能障碍与假设大脑高多巴胺能活动的既定多巴胺假说之间的关系。连续的部分验证了应用d -丝氨酸和其他作用于NMDA受体甘氨酸位点的激动剂来开发NMDA受体活性增强治疗精神分裂症的原理,并概述了使用这些激动剂的临床前和临床研究。NMDA受体靶向策略受到了结果的挑战,即增加细胞外甘氨酸浓度的附加治疗未能改善精神分裂症患者的抗精神病难治症状。为了解决这个问题,后一部分提出了通过修改构成细胞外水平d -丝氨酸代谢途径和调节系统的分子来上调突触内源性d -丝氨酸信号传导,从而恢复前脑NMDA受体功能的可能性。
Based on the glutamate hypothesis of schizophrenia postulating hypofunction of theN-methyl-D-aspartate type glutamate receptor (NMDA receptor) consisting of GluN1 and GluN2 subunits, D-serine has been selected as a candidate agent that is expected to satisfy an unmet need to ameliorate antipsychotic-resistant negative and cognitive symptoms in schizophrenia by recovering the NMDA receptor disturbance as one of its coagonists. Meta-analyses of randomized controlled trials of D-serine given with currently available antipsychotic drugs in patients with schizophrenia have consistently shown a significant reduction in the rating scores of their negative symptoms although D-serine has not yet been approved for clinical use. This chapter begins with verification of the evidence for the involvement of diminished NMDA receptor-mediated transmission in the pathophysiology of schizophrenia, accumulated data illustrating the plausible mechanisms from the hypofunction to the positive, negative, and cognitive symptoms and the relationships between the NMDA dysfunction and the well-established dopamine hypothesis assuming cerebral hyperdopaminergic activities. The consecutive parts verify the rationales for application of D-serine and other agonists acting at the glycine site of the NMDA receptor for development of NMDA receptor activity-enhancing therapy of schizophrenia and outline the preclinical and clinical studies using these agonists. The NMDA receptor targeting strategy is challenged by the results that the add-on treatments with augmentation of the extracellular glycine concentrations have failed to improve the antipsychotic-refractory symptoms of schizophrenia patients. To address this issue, the latter parts raise the possibility to restore functioning of the forebrain NMDA receptor by upregulating endogenous D-serine signaling at the synapses by modifying the molecules that compose the metabolic pathways and regulatory systems of the extracellular levels of D-serine.
DOI: 10.1073/pnas.1909458116
发表时间: 2019-10-08
影响因子: 11.1
作者:
Neame, Samah;Safory, Hazem;Wolosker, Herman
通讯作者: Wolosker, Herman
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发表时间: 2000-11-01
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期刊: BRAIN
影响因子: 14.5
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DOI: 10.1111/j.1471-4159.1984.tb02718.x
发表时间: 1984
影响因子: 4.7
作者:
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