药物神经毒性非临床安全性评价方法和技术概述

Overview of nonclinical safety evaluation methods and techniques for drug-induced neurotoxicity

药物神经毒性非临床安全性评价是早期筛选神经毒性药物及降低药物研发风险的重要手段,而且能为后续的临床试验提供毒性证据支持。原国家食品药品监督管理总局(China Food and Drug Administration,CFDA)、经济合作与发展组织(Organization for Economic Co-operation and Development,OECD)的药物非临床安全性评价指导原则中涉及神经毒性及发育神经毒性研究的一般方法为啮齿类动物及非人灵长类动物实验的组织病理学检查和神经行为学检查。至今,动物实验技术已经从传统的显微镜微观检查形态发展到活体成像技术。随着国内外倡导动物福利和3R原则,即减少(reduction)、替代(replacement)和优化(refinement),以及体外替代模型的不断出现,将各种体外评价方法和技术,如神经细胞成像技术、神经电生理技术、组学技术等,经过验证后用于监管科学领域已成为国内外药物非临床安全性评价工作者努力的方向。但是,无论是体内试验还是体外替代方法都无法全面评价神经毒物的潜在风险,因此只有将适合的方法有效地结合才能在非临床准确、高效地评价药物的神经毒性。

Nonclinical safety evaluation of drug-induced neurotoxicity is an important approach to early screen neurotoxicants and reduce the risk of drug development,and can provide toxicological evidence to support the subsequent clinical trials. The general methods involved in neurotoxicity and developmental neurotoxicity studies in the CFDA and OECD guidelines for nonclinical safety evaluation are to conduct histopathological examination and neurobehavioral examination on rodents and non-human primates. So far,animal experimental technology has evolved from traditional microscopic examination of microscopic morphology to in vivo imaging technology. With international advocacy of animal welfare and 3R principles,as well as the continuous emergence of in vitro alternative models,various in vitro evaluation methods and technologies will be validated,such as cell imaging technology,electrophysiological technology,omics technology,etc,and the application of which in the field of regulatory science has become the direction of efforts of nonclinical safety evaluation workers. However,neither in vivo studies nor in vitro alternative method can comprehensively evaluate the potential risks of neurotoxicants,so the effective combination of these appropriate methods can accurately and efficiently evaluate the drug-induced neurotoxicity in nonclinical safety study.