钾通道在帕金森病中的潜在作用:发病机制和创新的治疗分子靶点。

IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pharmacological Reviews Pub Date : 2023-07-01 DOI:10.1124/pharmrev.122.000743
Xiaoyi Chen, Yunjiang Feng, Ronald J Quinn, Dean L Pountney, Des R Richardson, George D Mellick, Linlin Ma
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引用次数: 8

摘要

帕金森病(PD)是一种神经退行性疾病,其特征是中脑黑质致密部(SNpc)区域多巴胺能神经元的选择性丧失。神经元的丧失导致纹状体中多巴胺的减少,这是帕金森病核心运动症状的基础。到目前为止,还没有有效的治疗方法来阻止、减缓或逆转多巴胺能神经变性的病理进展。这种不幸的困境是由于目前对PD发病机制的生物学靶点和途径的了解尚处于早期阶段。离子通道因其在神经功能和神经炎症中的重要作用而成为PD治疗的新靶点。钾离子通道是最重要的离子通道家族,由于其在调节神经元兴奋性、神经递质释放、突触传递和神经炎症方面的作用,已被证明在PD病理中至关重要。在这篇综述中,描述了电压门控K+通道亚家族的成员,向内整流K+通道和Ca2+激活的K+通道。本文讨论了这些通道在PD病因学中作用的证据,以及相关病理机制的最新观点,以及它们作为PD神经保护药物开发的生物学靶点的潜力。意义声明:帕金森病(PD)是第二常见的神经退行性疾病,以中脑多巴胺能神经元进行性变性为特征。它是一种多因素疾病,涉及多种危险因素和复杂的病理生物学机制。越来越多的证据表明,离子通道通过调节神经元兴奋性和免疫细胞功能,在PD的发病和进展中发挥重要作用。因此,它们已成为PD的“热门”生物学靶点,多项针对PD治疗的候选药物的临床试验证明了这一点。
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Potassium Channels in Parkinson's Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the midbrain. The loss of neurons results in a subsequent reduction of dopamine in the striatum, which underlies the core motor symptoms of PD. To date, there are no effective treatments to stop, slow, or reverse the pathologic progression of dopaminergic neurodegeneration. This unfortunate predicament is because of the current early stages in understanding the biologic targets and pathways involved in PD pathogenesis. Ion channels have become emerging targets for new therapeutic development for PD due to their essential roles in neuronal function and neuroinflammation. Potassium channels are the most prominent ion channel family and have been shown to be critically important in PD pathology because of their roles in modulating neuronal excitability, neurotransmitter release, synaptic transmission, and neuroinflammation. In this review, members of the subfamilies of voltage-gated K+ channels, inward rectifying K+ channels, and Ca2+-activated K+ channels are described. Evidence of the role of these channels in PD etiology is discussed together with the latest views on related pathologic mechanisms and their potential as biologic targets for developing neuroprotective drugs for PD. SIGNIFICANCE STATEMENT: Parkinson's disease (PD) is the second most common neurodegenerative disorder, featuring progressive degeneration of dopaminergic neurons in the midbrain. It is a multifactorial disease involving multiple risk factors and complex pathobiological mechanisms. Mounting evidence suggests that ion channels play vital roles in the pathogenesis and progression of PD by regulating neuronal excitability and immune cell function. Therefore, they have become "hot" biological targets for PD, as demonstrated by multiple clinical trials of drug candidates targeting ion channels for PD therapy.

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来源期刊
Pharmacological Reviews
Pharmacological Reviews 医学-药学
CiteScore
34.70
自引率
0.50%
发文量
40
期刊介绍: Pharmacological Reviews is a highly popular and well-received journal that has a long and rich history of success. It was first published in 1949 and is currently published bimonthly online by the American Society for Pharmacology and Experimental Therapeutics. The journal is indexed or abstracted by various databases, including Biological Abstracts, BIOSIS Previews Database, Biosciences Information Service, Current Contents/Life Sciences, EMBASE/Excerpta Medica, Index Medicus, Index to Scientific Reviews, Medical Documentation Service, Reference Update, Research Alerts, Science Citation Index, and SciSearch. Pharmacological Reviews offers comprehensive reviews of new pharmacological fields and is able to stay up-to-date with published content. Overall, it is highly regarded by scholars.
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