系统阐述目前国内外神经毒性评价的相关策略及监管指南。伴随急性毒性研究、慢性毒性研究、发育/生殖毒性研究所开展的一般神经毒性评价依循OECD和ICH多项准则，主要通过动物体内的神经行为学检查和组织病理学检查方法进行评估。注重多方面观察指标，警惕假阳性干扰。分层评价策略针对大量筛选化合物，首先排除不太可能具有神经毒性的物质，减少资源浪费。通过危害识别、靶点或作用机制确认和有害结局路径（AOP）框架评估3个层次完成评价。对于一些神经毒性评价药物其临床前动物实验的给药方式比较特殊，如颅内注射给药，研究者需关注特殊给药方式的评价特点和风险。沿用体内评价方法的同时，体外模型在神经毒性评价中也应用已久并不断发展新的体外模型。类器官因优势明显成为更好选择，类器官智能领域为神经毒性评价带来新方向。总之，这些评价策略与方法有助于提高对神经毒性的识别与管理水平，为药物研发和安全性评估提供重要参考。

Systematically elucidates the key aspects of current strategies and regulatory guidelines for neurotoxicity evaluation in global drug development. Routine neurotoxicity assessment conducted alongside acute toxicity studies, chronic toxicity studies, and developmental/reproductive toxicity investigations typically adhere to multiple OECD（Organization for Economic Co-operation and Development） and ICH（International Council for Harmonisation of Technical Requiremens for Pharmaceuticals for Human Use） guidelines, primarily employing neurobehavioral examinations and histopathological analyses in animal models. A multi-parametric observation system is emphasized to minimize false-positive interference. A tiered evaluation approach can effectively screen substances, thereby reducing resource expenditure. The evaluation is completed through three levels: hazard identification, target or mode of action confirmation, and adverse outcome pathway framework assessment. Special administration routes（e.g., intracranial injection） in preclinical studies require protocol customization to address unique pharmacokinetic characteristics and risk profiles. While traditional in vivo methods remain fundamental, in vitro models have evolved significantly through technological advancements. Organoids, due to their demonstrable benefits, are emerging as a superior alternative. The application of “organoid intelligence” promises to open new avenues for neurotoxicity assessment. In conclusion, these evaluation strategies and methodologies contribute to enhanced identification and management of neurotoxic potential,ultimately providing essential benchmarks for drug development and safety assessment..

R285.5

干细胞及其衍生物创新药非临床评价关键技术研究资助项目(2024YFA1107302)