实验动物与比较医学

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自发性脑出血动物模型选择及临床前药物试验指南(2024年版)

  

  • 收稿日期:2024-01-02 修回日期:2024-02-15 出版日期:2024-02-26
  • 通讯作者: 张化彪 (1969—),男,博士,副主任医师,副教授,研究方向:神经病学和介入神经放射学的临床、教学和科研。E-mail: zhanghuabiao@yeah.net. ORCID:0009-0002-1094-0891
    何 纲 (1966—),男,博士,主任医师,教授,研究方向:中西医结合脑血管病基础和临床研究。E-mail:hegangdoctor@126.com. ORCID: 0009-0005-5102-6264;
    韩新巍(1958—),男,博士,主任医师,教授,研究方向:各类疾病的影像学诊断与介入放射学理论和临床,E-mail:hanxinwei2006@163.com. ORCID:0000-0003-4407-4864
    李英俊 (1974—),男,博士,教授,研究方向:病理学与病理生理学。E-mail:bjthst@163.com. ORCID:

Guidelines for the Selection of Animal Models and Preclinical Drug Trials for Spontaneous Intracerebral Hemorrhage (2024 Edition)

摘要:

自发性脑出血(spontaneous intracerebral hemorrhage,sICH)是最常见和致死性最高的卒中类型,其特征是脑实质的自发性出血,目前尚无有效的防治方法。现有的sICH动物模型可以概括为三大类:(1)诱导性脑出血模型,主要有自体血注入、胶原酶注射、微气球充盈、高血糖诱导的sICH血肿扩大模型;(2)自发性高血压脑出血模型,主要有易卒中性自发性高血压大鼠和易卒中性肾血管性高血压大鼠模型;(3)基因修饰模型,主要有高血压小鼠自发性脑实质出血模型、淀粉样脑血管病相关基因修饰sICH模型、动静脉畸形病变相关基因修饰动物模型及胶原蛋白相关基因修饰sICH模型。这些模型不仅帮助我们了解sICH的发病机制、探索预防或治疗的方法,也可用于临床前药物试验,促进sICH新药研发工作。本指南系统总结了sICH的发病机制,详细介绍了不同种属建模动物的优劣性、不同sICH动物模型的建模原理和方法、建模技术细节、模拟的病理生理机制及其临床相关性以及sICH动物模型神经行为评价技术,并比较了各种sICH模型的优缺点及其适用的研究范围,最后重点概括了sICH相关的临床前药物试验设计要点。

关键词: 指南, 自发性脑出血, 动物模型, 临床前药物试验

Abstract:

Spontaneous cerebral hemorrhage (sICH), the most prevalent and lethal subtype of strokes, is characterized by spontaneous hemorrhage in the brain parenchyma. Presently, there exists no effective prevention and treatment method for sICH. The extant sICH animal models can be broadly categorized into three classes: (1) induced intracerebral hemorrhage models including autologous blood injection, collagenase injection, microballoon inflation model, and hyperglycemia-induced ICH hematoma expansion model; (2) spontaneous hypertensive intracerebral hemorrhage models mainly including stroke-prone spontaneously hypertensive rats (SHRsp) and stroke-prone renovascular hypertension rats (RHRsp); (3) gene-modificatd models encompassing spontaneous cerebral parenchymal hemorrhage in hypertensive mice, cerebral amyloid angiopathy-related, arteriovenous malformation-related, and collagen-related genetically modified animal models for sICH. These models contribute not only to unraveling the pathogenesis of sICH and exploring preventive or therapeutic interventions but also serve as invaluable tools for conducting preclinical drug trials to advance novel treatments. This guide comprehensively reviews sICH pathogenesis, delineates the superiority and inferiority of different species of modeling animals, the modeling principles and techniques for various sICH animal models, elucidates the technical details of animal models production, summarizes the pathophysiological mechanism simulated by the models and their clinical relevance, outlines the neurobehavioral evaluation methodologies for sICH animal models, compares the advantages and disadvantages of various models, and suggests their applicable research areas. Additionally,we underscores critical considerations in the design of preclinical drug trials for sICH.

Key words: Guidelines, Spontaneous intracerebral hemorrhage, Animal models, Preclinical drug trials

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