帕金森病中由钙蛋白酶介导的神经变性

IF 0.5 4区 医学 Q4 NEUROSCIENCES
V. H. Knaryan
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引用次数: 0

摘要

摘要 帕金森病(Parkinson's disease,PD)是一种神经退行性运动障碍疾病,临床表现为运动功能障碍和非运动症状,由黑质多巴胺能神经元以及中枢和周围神经系统特定区域的神经元进行性变性引起。帕金森病的发病机制是多方面的,与持续的线粒体功能障碍、氧化应激、Са2+平衡失常有关,这些因素导致Са2+依赖性蛋白酶钙蛋白酶的活化。钙蛋白酶在神经元信号传导机制中发挥作用,确保细胞内神经化学和神经生理过程的正常进行。在神经病理学条件下,细胞内 Ca2+ 的升高和钙蛋白酶的激活、内源性钙蛋白酶的下调和/或外源性钙蛋白酶药物抑制剂的缺失,都会促使钙蛋白酶介导的凋亡途径激活,从而导致大脑中选择性脆弱的黑质多巴胺能神经元变性和丢失。我们已经证明,在实验性(体内、体外)和人类(死后)帕金森病中,脊髓背侧神经元和腹侧运动神经元也会通过钙蛋白酶介导的神经变性机制受到影响。合成的钙蛋白酶抑制剂--钙蛋白酶、SNJ1945和SJA6017--在脑和脊髓(体内、体外)中表现出神经保护作用,表明钙蛋白酶是药物治疗帕金森病脑和脊髓的潜在靶分子。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Calpain Mediated Neurodegeneration in Parkinson’s disease

Abstract

Parkinson’s disease (PD), a neurodegenerative movement disorder, is clinically manifested by disturbances in motor functions and non-motor symptoms, caused by progressive degeneration of nigrostriatal dopaminergic neurons and neurons in selected areas of the central and peripheral nervous system. The multifaceted pathogenesis of PD is associated with sustained mitochondrial dysfunction, oxidative stress, aberrant Са2+ homeostasis, which contribute to the activation of Са2+-dependent protease calpain. Calpain plays role in neuronal signaling mechanisms, ensuring the normal course of intracellular neurochemical and neurophysiological processes. In neuropathological conditions, elevation of intracellular Ca2+ and calpain activation, downregulation of endogenous and/or absence of exogenous pharmacological inhibitors of calpain, instigate calpain-mediated activation of apoptotic pathways, leading to degeneration and loss of selectively vulnerable nigrostriatal dopaminergic neurons in the brain. We have shown that at experimental (in vivo, in vitro) and human (postmortem) PD dorsal neurons and ventral motoneurons of the spinal cord are also affected through the calpain-mediated mechanisms of neurodegeneration. Synthetic calpain inhibitors – calpeptin, SNJ1945, and SJA6017, exhibited neuroprotective effects in the brain and spinal cord (in vivo, in vitro), suggesting calpain as a prospective target molecule for pharmacological therapy in the brain and spinal cord at PD.

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来源期刊
Neurochemical Journal
Neurochemical Journal 医学-神经科学
自引率
20.00%
发文量
40
审稿时长
>12 weeks
期刊介绍: Neurochemical Journal (Neirokhimiya) provides a source for the communication of the latest findings in all areas of contemporary neurochemistry and other fields of relevance (including molecular biology, biochemistry, physiology, neuroimmunology, pharmacology) in an afford to expand our understanding of the functions of the nervous system. The journal presents papers on functional neurochemistry, nervous system receptors, neurotransmitters, myelin, chromaffin granules and other components of the nervous system, as well as neurophysiological and clinical aspects, behavioral reactions, etc. Relevant topics include structure and function of the nervous system proteins, neuropeptides, nucleic acids, nucleotides, lipids, and other biologically active components. The journal is devoted to the rapid publication of regular papers containing the results of original research, reviews highlighting major developments in neurochemistry, short communications, new experimental studies that use neurochemical methodology, descriptions of new methods of value for neurochemistry, theoretical material suggesting novel principles and approaches to neurochemical problems, presentations of new hypotheses and significant findings, discussions, chronicles of congresses, meetings, and conferences with short presentations of the most sensational and timely reports, information on the activity of the Russian and International Neurochemical Societies, as well as advertisements of reagents and equipment.
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