摘要
虽然肌萎缩侧索硬化症(ALS)产生的潜在病理基础还没有被完全阐述,但是对ALS发病机理的认知已经取得了重大进展,证据显示了遗传因素和重要分子通路之间复杂的相互作用。谷氨酸介导的兴奋性毒性是ALS的病理生理学途径,且被鉴定为治疗性生物标记物,导致了目前用于ALS疾病修饰治疗的仅有的药理基础的发展。最近,通过动物模型的Na+ 通道阻滞剂的神经保护作用,提出和强调了一种ALS发病机理的电压门控持久Na+通道的假定作用。此外,在ALS遗传学方面取得的进步已经促进了病理生理过程中ALS新的潜在药物靶点的识别。基因治疗,包括反义寡核苷酸方法,已经在ALS动物模型中显示产生了神经保护作用;并且完成的I期人体试验证明了此治疗方法的可行性。该综述对ALS发病机理取得的进步进行了总结,强调了对于ALS药物开发作为潜在靶点的这些机理过程的重要性。
关键词: 肌萎缩侧索硬化症;临床试验;兴奋毒性;谷氨酸;运动神经元疾病;利鲁唑
Current Medicinal Chemistry
Title:Biomarkers and Future Targets for Development in Amyotrophic Lateral Sclerosis
Volume: 21 Issue: 31
Author(s): Parvathi Menon, Matthew C. Kiernan and Steve Vucic
Affiliation:
关键词: 肌萎缩侧索硬化症;临床试验;兴奋毒性;谷氨酸;运动神经元疾病;利鲁唑
摘要: Although the pathophysiological mechanisms underlying the development of amyotrophic lateral sclerosis (ALS) remain to be fully elucidated, there have been significant advances in the understanding of ALS pathogenesis, with evidence emerging of a complex interaction between genetic factors and dysfunction of vital molecular pathways. Glutamate- mediated excitoxicity is an important pathophysiological pathway in ALS, and was identified as an important therapeutic biomarker leading to development of the only pharmacologically based disease-modifying treatment currently available for ALS. More recently, a putative role of voltage-gated persistent Na+ channels in ALS pathogenesis has been suggested and underscored by neuroprotective effects of Na+ channel blocking agents in animal models. In addition, advances in ALS genetics have lead to identification of novel pathophysiological processes that could potentially serve as therapeutic targets in ALS. Genetic therapies, including antisense oligonucleotide approaches have been shown to exert neuroprotective effects in animal models of ALS, and Phase I human trial have been completed demonstrating the feasibility of such a therapeutic approach. The present review summarises the advances in ALS pathogenesis, emphasising the importance of these processes as potential targets for drug development in ALS.
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Cite this article as:
Menon Parvathi, Kiernan C. Matthew and Vucic Steve, Biomarkers and Future Targets for Development in Amyotrophic Lateral Sclerosis, Current Medicinal Chemistry 2014; 21 (31) . https://dx.doi.org/10.2174/0929867321666140601161148
DOI https://dx.doi.org/10.2174/0929867321666140601161148 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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