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）

doi:10.12300/j.issn.1674-5817.2024.001

实验动物与比较医学 ›› 2024, Vol. 44 ›› Issue (1): 3-30.DOI: 10.12300/j.issn.1674-5817.2024.001

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）

中国研究型医院学会医学动物实验专家委员会

收稿日期:2024-01-02 修回日期:2024-02-15 出版日期:2024-03-07 发布日期:2024-02-25
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：0009-0003-5971-6599

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

Committee of Experts on Medical Animal Experiments, Chinese Research Hospital Association

Received:2024-01-02 Revised:2024-02-15 Published:2024-02-25 Online:2024-03-07
Contact: ZHANG Huabiao (ORCID: 0009-0002-1094-0891), E-mail: zhanghuabiao@yeah.net;
HE Gang (ORCID: 0009-0005-5102-6264), E-mail: hegangdoctor@126.com;
HAN Xinwei （ORCID：0000-0003-4407-4864）， E-mail： hanxinwei2006@163.com；
LI Yingjun （ORCID：0009-0003-5971-6599）， E-mail： bjthst@163.com

摘要/Abstract

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，主要有高血压脑出血转基因模型、脑淀粉样血管病转基因模型、脑动静脉畸形病变相关基因修饰模型、脑海绵状血管畸形相关基因修饰模型及胶原蛋白相关基因修饰模型。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: 自发性脑出血, 卒中, 动物模型, 临床前药物试验

Abstract:

Spontaneous intracerebral hemorrhage (sICH), the most prevalent and lethal subtype of stroke, is characterized by spontaneous hemorrhage in the brain parenchyma. Presently, there are no effective methods for preventing and treating sICH. The existing sICH animal models can be broadly categorized into three classes: (1) induced intracerebral hemorrhage models, including autologous blood injection model, collagenase injection model, microballoon inflation model, and hyperglycemia-induced sICH hematoma expansion model; (2) spontaneous hypertensive intracerebral hemorrhage models mainly include stroke-prone spontaneously hypertensive rats (SHRsp) and stroke-prone renovascular hypertensive rats (RHRsp); (3) gene-modified models encompassing transgenic hypertensive intracerebral hemorrhage, transgenic cerebral amyloid angiopathy, arteriovenous malformation-related, cerebral cavernous 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, explains the modeling principles and techniques for various sICH animal models, elucidates the technical details of animal model 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, it underscores critical considerations in the design of preclinical drug trials for sICH.

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

中图分类号:

R-332

中国研究型医院学会医学动物实验专家委员会. 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）[J]. 实验动物与比较医学, 2024, 44(1): 3-30.

Committee of Experts on Medical Animal Experiments, Chinese Research Hospital Association. Guidelines for the Selection of Animal Models and Preclinical Drug Trials for Spontaneous Intracerebral Hemorrhage (2024 Edition)[J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 3-30.

图/表 9

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模型类别及构建方法 Model categories & construction methods	优点 Advantages	缺点 Disadvantages
自发性高血压脑出血R⁺/A⁺双转基因模型：给予高盐饮食和含L-NAME的饮用水，诱导R⁺/A⁺双转基因自发性高血压小鼠产生更严重的高血压，从而引发sICH^[12]	模型小鼠出血位置为脑干、基底节和小脑，与人类sICH部位相似^[12]。是研究临床sICH较理想的基因修饰动物模型	（1）造模药物不仅对小鼠肾脏和心脏有影响，也会影响在该模型上试验新药的药代动力学和药效学^[18]；（2）培育时间长，小鼠需超过10月龄才能发生sICH^[18]
脑淀粉样血管病脑出血转基因模型：用过表达APP的转基因小鼠建立了5种脑淀粉样血管病模型^[18]，包括APP23转基因小鼠、Tg-SwDI转基因小鼠、APP Dutch转基因小鼠、Tg2576转基因小鼠和ADanPP7转基因小鼠	（1）适用于脑淀粉样血管病相关sICH和小动脉完整性的分子机制研究^{[18, 112]}；（2）APP23转基因模型小鼠在27月龄可发生反复和较大量的出血，是研究脑淀粉样血管病相关sICH较理想的模型^[113-114]	（1）缺乏sICH表型的具体描述，且无法比较不同模型的严重程度^[18]；（2）仅ADanPP7转基因小鼠模型被报道出现过出血相关症状，其他4种模型的出血量均较小^[120]
动静脉畸形脑出血基因工程模型：（1）Alk1条件性基因敲除小鼠^[126]；（2）Kras条件性基因敲入小鼠^[127]；（3）Notch4基因相关基因敲除小鼠^[124]；（4）MGP基因敲除小鼠^[131]；（5）Rbpj基因敲除小鼠^[132]；（6）Itgb8和smad4条件性基因敲除小鼠^[133]；（7）Endoglin基因敲除小鼠^[130]	可用于研究脑动静脉畸形血管易损伤的分子机制^[125]	（1）制作困难，价格高昂，死亡率高，使用较少；（2）缺乏对sICH表型的细节描述^[139]
脑海绵状血管畸形相关基因修饰模型：（1）Ccm2基因相关脑海绵状血管畸形模型^[137]；（2）Ccm1^+/-/Msh2^-/-双基因敲除小鼠模型^[140]	可用于研究脑海绵状血管畸形的分子机制	（1）制作困难，价格高昂，死亡率高，使用较少；（2）部分模型缺乏对sICH表型细节描述
胶原蛋白脑出血基因工程模型：Col4a1突变小鼠^[144]	可用于研究sICH的环境影响因素和遗传因素^[144]	多数小鼠在早期死亡；存活小鼠在胚胎期即可发生sICH，且随年龄增大而加重^[144]

模型类别及构建方法 Model categories & construction methods	优点 Advantages	缺点 Disadvantages
自发性高血压脑出血R⁺/A⁺双转基因模型：给予高盐饮食和含L-NAME的饮用水，诱导R⁺/A⁺双转基因自发性高血压小鼠产生更严重的高血压，从而引发sICH^[12]	模型小鼠出血位置为脑干、基底节和小脑，与人类sICH部位相似^[12]。是研究临床sICH较理想的基因修饰动物模型	（1）造模药物不仅对小鼠肾脏和心脏有影响，也会影响在该模型上试验新药的药代动力学和药效学^[18]；（2）培育时间长，小鼠需超过10月龄才能发生sICH^[18]
脑淀粉样血管病脑出血转基因模型：用过表达APP的转基因小鼠建立了5种脑淀粉样血管病模型^[18]，包括APP23转基因小鼠、Tg-SwDI转基因小鼠、APP Dutch转基因小鼠、Tg2576转基因小鼠和ADanPP7转基因小鼠	（1）适用于脑淀粉样血管病相关sICH和小动脉完整性的分子机制研究^{[18, 112]}；（2）APP23转基因模型小鼠在27月龄可发生反复和较大量的出血，是研究脑淀粉样血管病相关sICH较理想的模型^[113-114]	（1）缺乏sICH表型的具体描述，且无法比较不同模型的严重程度^[18]；（2）仅ADanPP7转基因小鼠模型被报道出现过出血相关症状，其他4种模型的出血量均较小^[120]
动静脉畸形脑出血基因工程模型：（1）Alk1条件性基因敲除小鼠^[126]；（2）Kras条件性基因敲入小鼠^[127]；（3）Notch4基因相关基因敲除小鼠^[124]；（4）MGP基因敲除小鼠^[131]；（5）Rbpj基因敲除小鼠^[132]；（6）Itgb8和smad4条件性基因敲除小鼠^[133]；（7）Endoglin基因敲除小鼠^[130]	可用于研究脑动静脉畸形血管易损伤的分子机制^[125]	（1）制作困难，价格高昂，死亡率高，使用较少；（2）缺乏对sICH表型的细节描述^[139]
脑海绵状血管畸形相关基因修饰模型：（1）Ccm2基因相关脑海绵状血管畸形模型^[137]；（2）Ccm1^+/-/Msh2^-/-双基因敲除小鼠模型^[140]	可用于研究脑海绵状血管畸形的分子机制	（1）制作困难，价格高昂，死亡率高，使用较少；（2）部分模型缺乏对sICH表型细节描述
胶原蛋白脑出血基因工程模型：Col4a1突变小鼠^[144]	可用于研究sICH的环境影响因素和遗传因素^[144]	多数小鼠在早期死亡；存活小鼠在胚胎期即可发生sICH，且随年龄增大而加重^[144]

分类 Classification	等级 Grade	神经缺损表现 Manifestations of neural deficits
正常	0	未观察到神经缺损
中等	1	瘫痪侧前肢内收并屈曲于腹下（提尾悬空试验阳性）
严重	2	向瘫痪侧推动大鼠，阻力较正常侧降低（侧推试验阳性），没有向正常侧转圈行为
严重	3	除2级表现外，伴有向正常侧转圈行为，或爬行时向瘫痪侧倾倒
检测方法：提起大鼠的尾巴，使动物距离台面10 cm高，正常大鼠的前爪处于伸直状态，模型大鼠存在神经行为异常表现
等级说明：评价等级越高，说明神经损伤越严重
优点：（1）操作简单;（2）从整体上反映动物神经损伤程度，可进行定性和半定量评价
缺点：（1）检测方法相对粗糙和主观;（2）多用于早期神经损伤检测，不能全面反映远期神经损伤程度

分类 Classification	等级 Grade	神经缺损表现 Manifestations of neural deficits
正常	0	未观察到神经缺损
中等	1	瘫痪侧前肢内收并屈曲于腹下（提尾悬空试验阳性）
严重	2	向瘫痪侧推动大鼠，阻力较正常侧降低（侧推试验阳性），没有向正常侧转圈行为
严重	3	除2级表现外，伴有向正常侧转圈行为，或爬行时向瘫痪侧倾倒
检测方法：提起大鼠的尾巴，使动物距离台面10 cm高，正常大鼠的前爪处于伸直状态，模型大鼠存在神经行为异常表现
等级说明：评价等级越高，说明神经损伤越严重
优点：（1）操作简单;（2）从整体上反映动物神经损伤程度，可进行定性和半定量评价
缺点：（1）检测方法相对粗糙和主观;（2）多用于早期神经损伤检测，不能全面反映远期神经损伤程度

分类 Classification	神经缺损表现 Manifestations of neural deficits	评分 Scores
没有神经功能缺损	正常站立或爬行	0
轻度神经功能损伤	提尾时瘫痪侧前肢内收屈曲，不能完全伸展	1
中度神经功能损伤	爬行时向瘫痪侧转圈	2
重度神经功能损伤	站立或爬行时，向瘫痪侧摔倒	3
重度神经功能损伤	没有自发性爬行，伴意识水平降低	4
评分说明：（1）5级0～4分制评分系统。基础分为1分，如果没有基础分，则2～4分的评分视为无效。（2）分值越高，说明神经功能缺损越严重
优点：操作简单
缺点：（1）检测方法相对粗糙和主观；（2）仅用于检测早期神经功能损伤，不能反映远期神经功能损伤程度

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）

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

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神经缺损表现 Manifestations of neural deficits	评分 Scores
能够顺利爬过横杆，四肢完全发挥作用，无明显神经损害体征	7
能够爬过横杆，瘫痪肢体发挥作用＞50%	6
能够爬过横杆，瘫痪肢体发挥作用＜50%	5
不能顺利爬过横杆，跌落率＜50%	4
无法顺利爬过横杆，跌落率＞50%	3
不能在横杆上爬行，但可以坐在上面	2
根本爬不上横杆，无法将后腿放在水平位置，如果放在横杆上就会掉落下来	１
检测方法：将一根长度为80 cm、宽度为2.5 cm的横杆一端放在地下，另一端以60°角斜靠在墙面。逐个将动物放到木板上，通过观察动物在横杆上的行走能力评估其运动功能
评分说明：评分为1～7分，分值越小，说明神经功能缺损越严重。
优点：（1）装置简单，容易修改以适应不同测试需求；（2）可用于短期和长期运动功能损伤评估
缺点：（1）仅适用于较活跃的啮齿类动物，不适用于活动较少的动物；（2）测试方法未标准化，木条的宽度、长度、形状等均未统一

测试项目 Test item	神经缺损表现 Manifestations of neural deficits	评分 Scores
自主运动：观察动物在鼠笼内5 min的活动	活动正常	3
	轻度受限	2
	中度受限	1
	严重受限	0
体态对称性：提尾使之悬空，观察四肢状态	体态对称	3
	体态不对称	2
	偏瘫	1
前肢伸展功能：提尾悬空后肢，将前肢放在桌面，观察前肢伸展运动状况	对称	3
	轻度不对称	2
	显著不对称	1
	偏瘫	0
攀爬力和握力：攀爬和抓紧鼠笼的能力	攀爬容易，抓持有力	3
	攀爬困难，瘫痪侧抓持无力	2
	不能攀爬或转圈	1
双侧身体触觉	双侧对称	3
	瘫痪侧反应迟钝	2
	瘫痪侧无反应	1
双侧胡须触碰反应	对称	3
	不对称	2
	瘫痪侧无反应	1
评分说明：分值为4～18分，18分为正常。分值越大，表示神经功能损伤越轻
优点：综合评估运动、感觉、反射功能，可用于短期和长期神经功能评估
缺点：评价参数多，操作较复杂

测试项目 Test item	神经缺损表现 Manifestations of neural deficits	评分 Scores
运动功能：
（1）提尾试验	前肢屈曲	1
	后肢屈曲	1
	后头部在30 s内偏离垂直轴> 10°	1
（2）将大鼠放置于地板上	正常行走	0
	不能直线行走	1
	向偏瘫侧转圈	2
	向偏瘫侧倾倒	3
感觉功能：
（1）放置试验 (视觉和触觉测试)	离桌面10 cm处45°倾斜靠近桌面，反应延迟	1
（2）本体感觉试验（深感觉测试）	向桌子边缘压迫鼠爪刺激肢体肌肉, 无反应	1
（3）平衡木试验	稳定、平衡的姿势	0
	紧抓平衡木边缘	1
	紧抱平衡木，一侧肢体从平衡木垂落	2
	紧抱平衡木，双侧肢体从平衡木垂落，或在平衡木上转圈（> 60 s）	3
	试图在平衡木上保持平衡但跌落（> 40 s）	4
	试图在平衡木上保持平衡但跌落（> 20 s）	5
	跌落，或未尝试保持平衡，或挂在平衡木上（< 20 s）	6
反射功能：
（1）耳廓反射	接触外耳道时摇头	1
（2）角膜反射	用棉花轻触角膜时眨眼	1
（3）惊恐反射	对快弹硬纸板产生的短暂噪音有运动反应	1
（4）癫病、肌阵挛、肌张力减退	出现一种即得1分	1
评分说明：总分18分，评分越高，表示神经损伤越严重。13～18分为严重损伤；7～12分为中度损伤；1～6分为轻度伤害
优点：综合评估运动、感觉、反射和平衡功能，可用于长期神经功能缺损评估
缺点：（1）评价参数多，操作复杂；（2）仅适合评估基底节而非所有脑区神经功能缺损

测试项目 Test item	评分Scores
测试项目 Test item	3	2	1	0
自发活动（在常规鼠笼内观察5 min）	大鼠在笼盒里到处移动、探索环境、爬到鼠笼上缘≥3个侧面	大鼠在笼盒里笨拙地到处移动探索、爬到鼠笼上缘<3个侧面	重症大鼠根本没有向上爬行，在鼠笼里几乎没有移动	大鼠完全没有移动
肢体运动对称性（尾部悬挂）	四肢对称伸展	一侧肢体较对侧伸展更少或更慢	一侧肢体活动很少	一侧肢体完全没有移动（偏瘫）
前肢伸展（尾巴悬挂，前爪悬在桌子上）	双侧前肢伸直，用双侧前爪对称地行走	前爪行走受损，伸展不对称	一侧肢体活动很少	一侧肢体完全没有移动（偏瘫）
攀爬（在45°角的台面上进行）	牢牢抓紧鼠笼钢丝，很容易地爬到笼顶	肢体不对称地攀爬，或无力抓紧鼠笼钢丝	不能攀爬或只能转圈	大鼠完全没有移动
轴向感觉（从后背轻微刺激躯干）	对躯干两侧的刺激，大鼠都同样受到惊吓	一侧身体的反应慢于另一侧	对一侧躯体的刺激没有反应	一侧肢体完全没有移动（偏瘫）
本体振动感觉（从后背轻轻触摸）	对身体两侧的棉花束触碰，大鼠都会同样地转头	一侧身体的反应慢于另一侧	对一侧躯体的刺激没有反应	一侧肢体完全没有移动（偏瘫）
评分方法：通过6项功能测试，综合评估大鼠神经功能
评分说明：每项测试可能得分为0～3分，0分最差，3分最好。总分最低0分，最高18分
优点：一种专用于ICH大鼠模型的神经功能评价方法，可用于检测短期和长期的运动、感觉、平衡、认知等神经功能缺损
缺点：尚未见关于该评分系统缺点的报道

模型 Models	优势 Advantages	劣势 Disadvantages	适用研究领域 Applicable research areas
胶原酶诱导模型	（1）操作简单，重复性好，注射位置准确，出血量可控^[163]；（2）能够模拟sICH患者自然发生的持续出血和血肿扩张过程，脑组织学变化与人类一致，是最接近人类sICH的动物模型^[163]；（3）有典型的神经功能障碍，可作为评价脑出血后神经功能缺失和促功能恢复的干预手段效果评价的工具模型^[164]；（4）最适合大鼠和小鼠等小动物，并允许在转基因小鼠上应用^[163]；（5）已开发出胶原酶注射诱导猪ICH模型^[153]	（1）出血是弥漫性的，是胶原酶注射部位周围小血管破裂的结果，其血肿形成较慢^[165]；（2）胶原酶引起广泛的炎性反应^[165]，不适用于研究脑出血后的炎性反应机制；（3）胶原酶有细胞毒性作用^[164]，不能完全模拟人类sICH继发性损伤的病理生理	（1）常用于啮齿类动物模型，尤其适用于研究sICH病理生理机制，以及脑血肿形成和血肿扩张、血管源性水肿、血脑屏障损伤、轴突变性、细胞凋亡、内皮障碍和脑卒中后的全身并发症^[18]；（2）大鼠、小鼠模型尤其适合于sICH潜在治疗方法，如脑部超低温、人促红细胞生成素等的临床前研究，以及微小RNA、外泌体、纳米颗粒等新兴治疗探索等^{[6, 90-91, 166]}
自体血注入模型	（1）操作简单，重复性好，出血位置准确，出血量一致^[93-96]；（2）方法无菌且不使用外来物质，可模拟人类sICH自然出血和血液凝固过程^[93-96]；（3）适用于所有物种，其中大鼠和小鼠尾状核注血模型使用最普遍^[167]，并允许在转基因小鼠上应用。通过在额叶或基底神经节注射血液，已开发出兔、猫、犬、猪、羊、猴等多种大型动物模型^{[159, 168]}	（1）不是真正意义的血管破裂出血，不能模拟人类sICH的小血管破裂^[91]；（2）血液容易渗漏进入脑室和/或蛛网膜下腔，虽然两次和三次注血啮齿类动物模型解决了该问题，但增加了操作的复杂性^[94-96]；（3）该模型的神经功能障碍不明显，神经功能评分较低，因此神经学功能需要结合多种行为学评价方法来进行^[162]	（1）啮齿类模型尤其适合sICH后血液及血凝块毒性物质如凝血酶、红细胞、补体、氧化应激、细胞凋亡和促炎症级联反应在继发性脑损伤中的作用和机制研究^{[90-91, 169]}；（2）大鼠、小鼠模型适用于脑部超低温、干细胞等临床前研究，以及微小RNA、外泌体、纳米颗粒等新兴治疗探索等^{[6, 90]}；（3）兔模型被用于研究sICH成像技术、手术创新、药物治疗、麻醉药物对脑血流动力学和颅内压的影响，以及继发性损伤的病理生理机制等^[90]；（4）犬模型被用于研究sICH成像技术、脑生理学、新治疗方法，以及立体定向血肿抽吸手术的安全性和效果评估等^[90]；（5）猪模型^[170]临床相关性好，适用于sICH病理生理学和病理化学、水肿发展、血液成分的作用和脑组织代谢研究，以及组织纤溶酶原激活物（tPA）诱导血栓溶解后的药物和手术治疗效果评估，深部局部低温疗法、血红素加氧酶抑制剂等疗效评价等^[90]
微气球充盈模型	微气球充盈产生机械性占位效应，可模拟不同大小血肿对脑组织的压迫效果^[171]	（1）没有产生真实的血肿，不能模拟血液和随后血凝块释放物质引起的继发性脑损伤^[101]；（2）易造成不可逆脑损伤，无法评估继发性脑损伤^[171-174]	大鼠模型可用于评估占位效应、颅内压、脑血流量，以及血肿清除的效果等^{[101-102，172]}
高血糖诱导脑出血后血肿扩大模型	部分模拟了在糖尿病基础上发生sICH的临床情况^[103]	建模动物为年轻雄性小鼠，需进一步明确性别和年龄依赖性的影响^[103]	可用于糖尿病对sICH发生的影响、脑血肿扩大的原因和机制等研究^[175]
自发性高血压脑出血模型	（1）SHRsp与人类动脉硬化高血压sICH的病理生理和发病过程最接近^[104]；（2）RHRsp模型的血压峰值高，术后210 d内平均血压峰值为（17.2±1.1）kPa，存在与人类sICH相似的高血压动脉硬化病理生理基础^[105]	（1）SHRsp模型价格昂贵，来源困难，饲养困难，易变种及断种，实验时间长等^[104]；（2）RHRsp不是单纯的sICH模型，而是脑梗死、脑出血及混合性脑卒中并存^[105]；（3）重复性差，脑损伤大小和位置都不可预测^[104-105]	适用于sICH病理生理机制研究^[104-105]。该模型可以从以下几个方面进行药效评估：（1）RHRsp大鼠模型的生存期；（2）脑出血后运动功能障碍的改善情况；（3）脑系数；（4）组织形态学方法检测脑水肿程度、海马CA1区神经元变性和细胞数目；（5）脑出血后病灶吸收速度、小胶质细胞及毛细血管增生情况
基因修饰动物模型	（1）小鼠双转基因（R⁺/A⁺）高血压脑出血主要发生于基底节、脑干和小脑等部位^[12]，与人类sICH多发部位相似；（2）部分模型更能反映临床情况，如APP23转基因小鼠模型27月龄可发生反复及较大量的出血，可能是研究脑淀粉样血管病相关脑出血的最佳动物模型^[113-114]	（1）价格昂贵，制作困难，实验时间长，动物死亡率高^{[18，112，126]}；（2）转基因模型的出血时间、数量、大小和位置都不可预测，且无法比较不同模型脑出血的严重程度^{[18，112，126]}	（1）转基因啮齿类动物模型可用于研究sICH的基因发病机制及遗传因素对脑出血恢复的影响等^[18]；（2）转基因小鼠模型适用于特定疾病（如脑淀粉样血管病、动静脉畸形）相关性sICH研究^{[18，113-114，126]}

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