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

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 transgentic hypertensive intracerebral hemorrhage, transgentic 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

. 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.

图/表 9

参考文献 185

1	GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019[J]. Lancet Neurol, 2021, 20(10):795-820. DOI: 10.1016/S1474-4422(21)00252-0 .
2	QURESHI A I, MENDELOW A D, HANLEY D F. Intracerebral haemorrhage[J]. Lancet, 2009, 373(9675):1632-1644. DOI: 10. 1016/S0140-6736(09)60371-8 .
3	LIU M, WU B, WANG W Z, et al. Stroke in China: epidemiology, prevention, and management strategies[J]. Lancet Neurol, 2007, 6(5):456-464. DOI: 10.1016/S1474-4422(07)70004-2 .
4	VAN ASCH C J, LUITSE M J, RINKEL G J, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis[J]. Lancet Neurol, 2010, 9(2):167-176. DOI: 10.1016/S1474-4422(09)70340-0 .
5	FOGELHOLM R, MURROS K, RISSANEN A, et al. Long term survival after primary intracerebral haemorrhage: a retrospective population based study[J]. J Neurol Neurosurg Psychiatry, 2005, 76(11):1534-1538. DOI: 10.1136/jnnp.2004. 055145 .
6	ZILLE M, FARR T D, KEEP R F, et al. Novel targets, treatments, and advanced models for intracerebral haemorrhage[J]. EBioMedicine, 2022, 76:103880. DOI: 10.1016/j.ebiom.2022. 103880 .
7	O'COLLINS V E, MACLEOD M R, DONNAN G A, et al. 1, 026 experimental treatments in acute stroke[J]. Ann Neurol, 2006, 59(3):467-477. DOI: 10.1002/ana.20741 .
8	MYSERLIS E P, MAYERHOFER E, ABRAMSON J R, et al. Lobar intracerebral hemorrhage and risk of subsequent un-controlled blood pressure[J]. Eur Stroke J, 2022, 7(3):280-288. DOI: 10.1177/23969873221094412 .
9	WANG X, DI TANNA G L, MOULLAALI T J, et al. J-shape relation of blood pressure reduction and outcome in acute intracerebral hemorrhage: a pooled analysis of INTERACT2 and ATACH-II individual participant data[J]. Int J Stroke, 2022, 17(10):1129-1136. DOI: 10.1177/17474930211064076 .
10	SCHLEICHER R L, LI K R, MYLVAGANAM R, et al. Expression of DEspR in acute intracerebral hemorrhage[J]. J Stroke Cerebrovasc Dis, 2022, 31(10):106685. DOI: 10.1016/j.jstroke cerebrovasdis.2022.106685 .
11	HERRERA V L M, GROMISCH C M, DECANO J L, et al. Anti-DEspR antibody treatment improves survival and reduces neurologic deficits in a hypertensive, spontaneous intra-cerebral hemorrhage (hsICH) rat model[J]. Sci Rep, 2023, 13(1):2703. DOI: 10.1038/s41598-023-28149-3 .
12	IIDA S, BAUMBACH G L, LAVOIE J L, et al. Spontaneous stroke in a genetic model of hypertension in mice[J]. Stroke, 2005, 36(6):1253-1258. DOI: 10.1161/01.str.0000167694.58419.a2 .
13	CHEN Y H, CHANG J B, WEI J J, et al. Assessing the evolution of intracranial hematomas by using animal models: a review of the progress and the challenges[J]. Metab Brain Dis, 2021, 36(8):2205-2214. DOI: 10.1007/s11011-021-00828-y .
14	JEANNE M, JORGENSEN J, GOULD D B. Molecular and genetic analyses of collagen type IV mutant mouse models of spontaneous intracerebral hemorrhage identify mechanisms for stroke prevention[J]. Circulation, 2015, 131(18):1555-1565. DOI: 10.1161/CIRCULATIONAHA.114.013395 .
15	RATELADE J, KLUG N R, LOMBARDI D, et al. Reducing hypermuscularization of the transitional segment between arterioles and capillaries protects against spontaneous intracerebral hemorrhage[J]. Circulation, 2020, 141(25):2078-2094. DOI: 10.1161/CIRCULATIONAHA.119.040963 .
16	XIAO N, LIU T L, LI H, et al. Low serum uric acid levels promote hypertensive intracerebral hemorrhage by disrupting the smooth muscle cell-elastin contractile unit and upregulating the Erk1/2-MMP axis[J]. Transl Stroke Res, 2020, 11(5):1077-1094. DOI: 10.1007/s12975-020-00791-3 .
17	HOSTETTLER I C, SEIFFGE D J, WERRING D J. Intracerebral hemorrhage: an update on diagnosis and treatment[J]. Expert Rev Neurother, 2019, 19(7):679-694. DOI: 10.1080/14737175.2019.1623671 .
18	ALHARBI B M, TSO M K, MACDONALD R L. Animal models of spontaneous intracerebral hemorrhage[J]. Neurol Res, 2016, 38(5):448-455. DOI: 10.1080/01616412.2016.1144671 .
19	CANNISTRARO R J, MESCHIA J F. The clinical dilemma of anticoagulation use in patients with cerebral amyloid angiopathy and atrial fibrillation[J]. Curr Cardiol Rep, 2018, 20(11):106. DOI: 10.1007/s11886-018-1052-1 .
20	MALHOTRA K, THEODOROU A, KATSANOS A H, et al. Prevalence of clinical and neuroimaging markers in cerebral amyloid angiopathy: a systematic review and meta-analysis[J]. Stroke, 2022, 53(6):1944-1953. DOI: 10.1161/STROKEAHA. 121.035836 .
21	SANCHEZ-CARO J M, DE LORENZO MARTÍNEZ DE UBAGO I, DE CELIS RUIZ E, et al. Transient focal neurological events in cerebral amyloid angiopathy and the long-term risk of intracerebral hemorrhage and death: a systematic review and meta-analysis[J]. JAMA Neurol, 2022, 79(1):38-47. DOI: 10.1001/jamaneurol.2021.3989 .
22	HOSTETTLER I C, SEIFFGE D, WONG A, et al. APOE and cerebral small vessel disease markers in patients with intracerebral hemorrhage[J]. Neurology, 2022, 99(12): e1290-e1298. DOI: 10.1212/WNL.0000000000200851 .
23	BAI Y, DENG H, SHANTSILA A, et al. Rivaroxaban versus dabigatran or warfarin in real-world studies of stroke prevention in atrial fibrillation: systematic review and meta-analysis[J]. Stroke, 2017, 48(4):970-976. DOI: 10.1161/STROKEAHA.116.016275 .
24	WU T T, LV C Y, WU L S, et al. Risk of intracranial hemorrhage with direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials[J]. J Neurol, 2022, 269(2):664-675. DOI: 10.1007/s00415-021-10448-2 .
25	BUTCHER K S, NG K, SHERIDAN P, et al. Dabigatran treatment of acute noncardioembolic ischemic stroke[J]. Stroke, 2020, 51(4):1190-1198. DOI: 10.1161/STROKEAHA. 119.027569 .
26	COCHRANE A, CHEN C, STEPHEN J, et al. Antithrombotic treatment after stroke due to intracerebral haemorrhage[J]. Cochrane Database Syst Rev, 2023, 1(1): CD012144. DOI: 10.1002/14651858.CD012144.pub3 .
27	PÉTRAULT M, OUK T, PÉTRAULT O, et al. Safety of oral anticoagulants on experimental brain microbleeding and cognition[J]. Neuropharmacology, 2019, 155:162-172. DOI: 10.1016/j.neuropharm.2019.05.030 .
28	HILL C S, BORG A, HORSFALL H L, et al. Cerebral cavernous malformation: management, outcomes, and surveillance strategies - A single centre retrospective cohort study[J]. Clin Neurol Neurosurg, 2023, 225:107576. DOI: 10.1016/j.clineuro. 2022.107576 .
29	CARDOSO C, ARNOULD M, DE LUCA C, et al. Novel chronic mouse model of cerebral cavernous malformations[J]. Stroke, 2020, 51(4):1272-1278. DOI: 10.1161/STROKEAHA. 119.027207 .
30	CHOKSI F, WEINSHEIMER S, NELSON J, et al. Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation[J]. Mol Genet Genomic Med, 2021, 9(10): e1794. DOI: 10.1002/mgg3.1794 .
31	WEINSHEIMER S, NELSON J, ABLA A A, et al. Intracranial hemorrhage rate and lesion burden in patients with familial cerebral cavernous malformation[J]. J Am Heart Assoc, 2023, 12(3): e027572. DOI: 10.1161/JAHA.122.027572 .
32	VAN BEIJNUM J, VAN DER WORP H B, BUIS D R, et al. Treatment of brain arteriovenous malformations: a systematic review and meta-analysis[J]. JAMA, 2011, 306(18):2011-2019. DOI: 10.1001/jama.2011.1632 .
33	LI H, YAN Z H, HUO R, et al. RNA sequencing analysis between ruptured and un-ruptured brain AVM[J]. Chin Neurosurg J, 2022, 8(1):13. DOI: 10.1186/s41016-022-00282-4 .
34	LI Q F, DECKER-ROCKEFELLER B, BAJAJ A, et al. Activation of ras in the vascular endothelium induces brain vascular malformations and hemorrhagic stroke[J]. Cell Rep, 2018, 24(11):2869-2882. DOI: 10.1016/j.celrep.2018.08.025 .
35	NIKOLAEV S I, FISH J E, RADOVANOVIC I. Somatic activating KRAS mutations in arteriovenous malformations of the brain[J]. N Engl J Med, 2018, 378(16):1561-1562. DOI: 10.1056/NEJMc1802190 .
36	RIST P M, BURING J E, RIDKER P M, et al. Lipid levels and the risk of hemorrhagic stroke among women[J]. Neurology, 2019, 92(19): e2286-e2294. DOI: 10.1212/WNL. 000000000 0007454 .
37	KREL M, MIULLI D E, JUNG H, et al. Minimization of intraparenchymal hemorrhagic stroke size by optimization of serum lipids[J]. Cureus, 2019, 11(4): e4406. DOI: 10.7759/cureus.4406 .
38	MOUTZOURI E, GLUTZ M, ABOLHASSANI N, et al. Association of statin use and lipid levels with cerebral microbleeds and intracranial hemorrhage in patients with atrial fibrillation: a prospective cohort study[J]. Int J Stroke, 2023, 18(10):1219-1227. DOI: 10.1177/17474930231181010 .
39	LI Q, ZHANG G, XIONG X, et al. Black hole sign: novel imaging marker that predicts hematoma growth in patients with intracerebral hemorrhage[J]. Stroke, 2016, 47(7):1777-1781. DOI: 10.1161/STROKEAHA.116.013186 .
40	MOROTTI A, DOWLATSHAHI D, BOULOUIS G, et al. Predicting intracerebral hemorrhage expansion with noncontrast computed tomography: the BAT score[J]. Stroke, 2018, 49(5):1163-1169. DOI: 10.1161/STROKEAHA. 117.020138 .
41	WANG X, ARIMA H, SALMAN R A S, et al. Clinical prediction algorithm (BRAIN) to determine risk of hematoma growth in acute intracerebral hemorrhage[J]. Stroke, 2015, 46(2):376-381. DOI: 10.1161/STROKEAHA.114.006910 .
42	BROUWERS H B, CHANG Y, FALCONE G J, et al. Predicting hematoma expansion after primary intracerebral hemorrhage[J]. JAMA Neurol, 2014, 71(2):158-164. DOI: 10.1001/jamaneurol. 2013.5433 .
43	MAYER S A, BRUN N C, BEGTRUP K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage[J]. N Engl J Med, 2008, 358(20):2127-2137. DOI: 10.1056/NEJMoa0707534 .
44	VAN DER HORST S F B, MARTENS E S L, DEN EXTER P L, et al. Idarucizumab for dabigatran reversal: a systematic review and meta-analysis of indications and outcomes[J]. Thromb Res, 2023, 228:21-32. DOI: 10.1016/j.thromres.2023.05.020 .
45	CONNOLLY S J, MILLING T J Jr, EIKELBOOM J W, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors[J]. N Engl J Med, 2016, 375(12):1131-1141. DOI: 10.1056/NEJMoa1607887 .
46	CHU H L, GAO Z D, HUANG C Y, et al. Relationship between hematoma expansion induced by hypertension and hyperglycemia and blood-brain barrier disruption in mice and its possible mechanism: role of aquaporin-4 and Connexin43[J]. Neurosci Bull, 2020, 36(11):1369-1380. DOI: 10.1007/s12264-020-00540-4 .
47	SCHLUNK F, BÖHM M, BOULOUIS G, et al. Secondary bleeding during acute experimental intracerebral hemorrhage[J]. Stroke, 2019, 50(5):1210-1215. DOI: 10.1161/STROKEAHA.118.021732 .
48	MOROTTI A, SHOAMANESH A, OLIVEIRA-FILHO J, et al. White matter hyperintensities and blood pressure lowering in acute intracerebral hemorrhage: a secondary analysis of the ATACH-2 trial[J]. Neurocrit Care, 2020, 32(1):180-186. DOI: 10.1007/s12028-019-00761-0 .
49	KLAHR A C, KOSIOR J C, DOWLATSHAHI D, et al. Lower blood pressure is not associated with decreased arterial spin labeling estimates of perfusion in intracerebral hemorrhage[J]. J Am Heart Assoc, 2019, 8(11): e010904. DOI: 10.1161/JAHA.118.010904 .
50	SATTUR M G, SPIOTTA A M. Commentary: efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomized, controlled, open-label, blinded endpoint phase 3 trial[J]. Neurosurgery, 2020, 86(5): E444-E446. DOI: 10.1093/neuros/nyz551 .
51	CHANG C F, MASSEY J, OSHEROV A, et al. Bexarotene enhances macrophage erythrophagocytosis and hematoma clearance in experimental intracerebral hemorrhage[J]. Stroke, 2020, 51(2):612-618. DOI: 10.1161/STROKEAHA. 119.027037 .
52	XU J, CHEN Z Q, YU F, et al. IL-4/STAT6 signaling facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice[J]. Proc Natl Acad Sci USA, 2020, 117(51):32679-32690. DOI: 10.1073/pnas.2018497117 .
53	FU X J, ZHOU G Y, ZHUANG J F, et al. White matter injury after intracerebral hemorrhage[J]. Front Neurol, 2021, 12:562090. DOI: 10.3389/fneur.2021.562090 .
54	YANG Y, CHEN X Z, FENG Z Z, et al. MEC17-induced α-tubulin acetylation restores mitochondrial transport function and alleviates axonal injury after intracerebral hemorrhage in mice[J]. J Neurochem, 2022, 160(1):51-63. DOI: 10.1111/jnc. 15493 .
55	YANG H, NI W, WEI P J, et al. HDAC inhibition reduces white matter injury after intracerebral hemorrhage[J]. J Cereb Blood Flow Metab, 2021, 41(5): 958-974. DOI:10.1177/0271678X20942613 .
56	LI M X, XIA M, CHEN W X, et al. Lithium treatment mitigates white matter injury after intracerebral hemorrhage through brain-derived neurotrophic factor signaling in mice[J]. Transl Res, 2020, 217:61-74. DOI: 10.1016/j.trsl.2019.12.006 .
57	YANG Z Y, DONG S S, ZHENG Q Y, et al. FTY720 attenuates iron deposition and glial responses in improving delayed lesion and long-term outcomes of collagenase-induced intracerebral hemorrhage[J]. Brain Res, 2019, 1718:91-102. DOI: 10.1016/j.brainres.2019.04.031 .
58	FOUDA A Y, NEWSOME A S, SPELLICY S, et al. Minocycline in acute cerebral hemorrhage: an early phase randomized trial[J]. Stroke, 2017, 48(10):2885-2887. DOI: 10.1161/STROKEAHA. 117.018658 .
59	ZHOU S Y, CUI G Z, YAN X L, et al. Mechanism of ferroptosis and its relationships with other types of programmed cell death: insights for potential interventions after intracerebral hemorrhage[J]. Front Neurosci, 2020, 14:589042. DOI: 10.3389/fnins.2020.589042 .
60	CHEN B, CHEN Z H, LIU M J, et al. Inhibition of neuronal ferroptosis in the acute phase of intracerebral hemorrhage shows long-term cerebroprotective effects[J]. Brain Res Bull, 2019, 153:122-132. DOI: 10.1016/j.brainresbull.2019.08.013 .
61	SELIM M, FOSTER L D, MOY C S, et al. Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial[J]. Lancet Neurol, 2019, 18(5):428-438. DOI: 10.1016/S1474-4422(19)30069-9 .
62	JIA P J, HE J X, LI Z F, et al. Profiling of blood-brain barrier disruption in mouse intracerebral hemorrhage models: collagenase injection vs. autologous arterial whole blood infusion[J]. Front Cell Neurosci, 2021, 15:699736. DOI: 10.3389/fncel.2021.699736 .
63	BOLTZE J, FERRARA F, HAINSWORTH A H, et al. Lesional and perilesional tissue characterization by automated image processing in a novel gyrencephalic animal model of peracute intracerebral hemorrhage[J]. J Cereb Blood Flow Metab, 2019, 39(12):2521-2535. DOI: 10.1177/0271678X18802119 .
64	KUNG T F C, WILKINSON C M, DIRKS C A, et al. Glibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats[J]. PLoS One, 2021, 16(6): e0252584. DOI: 10.1371/journal.pone. 0252584 .
65	XUE M Z, YONG V W. Neuroinflammation in intracerebral haemorrhage: immunotherapies with potential for translation[J]. Lancet Neurol, 2020, 19(12):1023-1032. DOI: 10.1016/S1474-4422(20)30364-1 .
66	LI Z G, LI Y L, HAN J R, et al. Formyl peptide receptor 1 signaling potentiates inflammatory brain injury[J]. Sci Transl Med, 2021, 13(605): eabe9890. DOI: 10.1126/scitranslmed.abe9890 .
67	HE Y, GAO Y, ZHANG Q, et al. IL-4 switches microglia/macrophage M1/M2 polarization and alleviates neurological damage by modulating the JAK1/STAT6 pathway following ICH[J]. Neuroscience, 2020, 437:161-171. DOI: 10.1016/j.neuroscience.2020.03.008 .
68	BAI Q, XUE M Z, YONG V W. Microglia and macrophage phenotypes in intracerebral haemorrhage injury: therapeutic opportunities[J]. Brain, 2020, 143(5):1297-1314. DOI: 10.1093/brain/awz393 .
69	TSCHOE C, BUSHNELL C D, DUNCAN P W, et al. Neuroinflammation after intracerebral hemorrhage and potential therapeutic targets[J]. J Stroke, 2020, 22(1):29-46. DOI: 10.5853/jos.2019.02236 .
70	CARMONA-MORA P, ANDER B P, JICKLING G C, et al. Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke[J]. J Cereb Blood Flow Metab, 2021, 41(6):1398-1416. DOI: 10.1177/0271678X20953912 .
71	ZHAO X R, TING S M, LIU C H, et al. Neutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage[J]. Nat Commun, 2017, 8(1):602. DOI: 10.1038/s41467-017-00770-7 .
72	ZHAO X R, KRUZEL M, TING S M, et al. Optimized lactoferrin as a highly promising treatment for intracerebral hemorrhage: pre-clinical experience[J]. J Cereb Blood Flow Metab, 2021, 41(1):53-66. DOI: 10.1177/0271678X20925667 .
73	HAN R R, LUO J Y, SHI Y C, et al. PD-L1 (programmed death ligand 1) protects against experimental intracerebral hemorrhage-induced brain injury[J]. Stroke, 2017, 48(8):2255-2262. DOI: 10.1161/STROKEAHA.117.016705 .
74	CHENG N, WANG H, ZOU M, et al. Brain-derived programmed death-ligand 1 mediates immunosuppression post intracerebral hemorrhage[J]. J Cereb Blood Flow Metab, 2022, 42(11):2048-2057. DOI: 10.1177/0271678X221116048 .
75	ZHANG L, WANG H D. FTY720 in CNS injuries: molecular mechanisms and therapeutic potential[J]. Brain Res Bull, 2020, 164:75-82. DOI: 10.1016/j.brainresbull.2020.08.013 .
76	ZHANG L Q, WURI J, AN L L, et al. Metoprolol attenuates intracerebral hemorrhage-induced cardiac damage by suppression of sympathetic overactivity in mice[J]. Auton Neurosci, 2021, 234:102832. DOI: 10.1016/j.autneu.2021.102832 .
77	SONG J R, CHEN W J, YE W. Stroke and the risk of gastrointestinal disorders: a Mendelian randomization study[J]. Front Neurol, 2023, 14:1131250. DOI: 10.3389/fneur.2023. 1131250 .
78	ZHANG Y, YU W P, FLYNN C, et al. Interplay between gut microbiota and NLRP3 inflammasome in intracerebral hemorrhage[J]. Nutrients, 2022, 14(24):5251. DOI: 10.3390/nu14245251 .
79	YU X B, ZHOU G Y, SHAO B, et al. Gut microbiota dysbiosis induced by intracerebral hemorrhage aggravates neuroinflammation in mice[J]. Front Microbiol, 2021, 12:647304. DOI: 10.3389/fmicb.2021.647304 .
80	BAI Q, SHENG Z F, LIU Y, et al. Intracerebral haemorrhage: from clinical settings to animal models[J]. Stroke Vasc Neurol, 2020, 5(4):388-395. DOI: 10.1136/svn-2020-000334 .
81	PAIVA W S, ZIPPO E, MIRANDA C, et al. Animal models for the study of intracranial hematomas (Review)[J]. Exp Ther Med, 2022, 25(1):20. DOI: 10.3892/etm.2022.11719 .
82	ROSENBERG G A, ESTRADA E, KELLEY R O, et al. Bacterial collagenase disrupts extracellular matrix and opens blood-brain barrier in rat[J]. Neurosci Lett, 1993, 160(1):117-119. DOI: 10.1016/0304-3940(93)90927-d .
83	ROSENBERG G A, MUN-BRYCE S, WESLEY M, et al. Collagenase-induced intracerebral hemorrhage in rats[J]. Stroke, 1990, 21(5):801-807. DOI: 10.1161/01.str.21.5.801 .
84	CLARK W, GUNION-RINKER L, LESSOV N, et al. Citicoline treatment for experimental intracerebral hemorrhage in mice[J]. Stroke, 1998, 29(10):2136-2140. DOI: 10.1161/01.str.29. 10.2136 .
85	MACLELLAN C L, SILASI G, POON C C, et al. Intracerebral hemorrhage models in rat: comparing collagenase to blood infusion[J]. J Cereb Blood Flow Metab, 2008, 28(3):516-525. DOI: 10.1038/sj.jcbfm.9600548 .
86	TANAKA Y, MARUMO T, SHIBUTA H, et al. Serum S100B, brain edema, and hematoma formation in a rat model of collagenase-induced hemorrhagic stroke[J]. Brain Res Bull, 2009, 78(4-5):158-163. DOI: 10.1016/j.brainresbull.2008.10.012 .
87	MACLELLAN C L, DAVIES L M, FINGAS M S, et al. The influence of hypothermia on outcome after intracerebral hemorrhage in rats[J]. Stroke, 2006, 37(5):1266-1270. DOI: 10.1161/01.STR.0000217268.81963.78 .
88	DEL BIGIO M R, YAN H J, BUIST R, et al. Experimental intracerebral hemorrhage in rats. Magnetic resonance imaging and histopathological correlates[J]. Stroke, 1996, 27(12):2312-2319; discussion 2319-2320. DOI: 10.1161/01.str.27. 12.2312 .
89	BERAY-BERTHAT V, DELIFER C, BESSON V C, et al. Long-term histological and behavioural characterisation of a collagenase-induced model of intracerebral haemorrhage in rats[J]. J Neurosci Methods, 2010, 191(2):180-190. DOI: 10.1016/j.jneumeth.2010.06.025 .
90	JAMES M L, WARNER D S, LASKOWITZ D T. Preclinical models of intracerebral hemorrhage: a translational perspective[J]. Neurocrit Care, 2008, 9(1):139-152. DOI: 10. 1007/s12028-007-9030-2 .
91	ANDALUZ N, ZUCCARELLO M, WAGNER K R. Experimental animal models of intracerebral hemorrhage[J]. Neurosurg Clin N Am, 2002, 13(3):385-393. DOI: 10.1016/s1042-3680(02)00006-2 .
92	MA Q Y, KHATIBI N H, CHEN H, et al. History of preclinical models of intracerebral hemorrhage[J]. Acta Neurochir Suppl, 2011, 111:3-8. DOI: 10.1007/978-3-7091-0693-8_1 .
93	YANG G Y, BETZ A L, CHENEVERT T L, et al. Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats[J]. J Neurosurg, 1994, 81(1):93-102. DOI: 10.3171/jns. 1994.81.1.0093 .
94	DEINSBERGER W, VOGEL J, KUSCHINSKY W, et al. Experimental intracerebral hemorrhage: description of a double injection model in rats[J]. Neurol Res, 1996, 18(5):475-477. DOI: 10.1080/01616412.1996.11740456 .
95	BELAYEV L, SAUL I, CURBELO K, et al. Experimental intracerebral hemorrhage in the mouse: histological, behavioral, and hemodynamic characterization of a double-injection model[J]. Stroke, 2003, 34(9):2221-2227. DOI: 10.1161/01.STR.0000088061.06656.1E .
96	MA B, ZHANG J. Nimodipine treatment to assess a modified mouse model of intracerebral hemorrhage[J]. Brain Res, 2006, 1078(1):182-188. DOI: 10.1016/j.brainres.2006.01.045 .
97	KNIGHT R A, HAN Y X, NAGARAJA T N, et al. Temporal MRI assessment of intracerebral hemorrhage in rats[J]. Stroke, 2008, 39(9):2596-2602. DOI: 10.1161/STROKEAHA.107.506683 .
98	XUE M, DEL BIGIO M R. Intracerebral injection of autologous whole blood in rats: time course of inflammation and cell death[J]. Neurosci Lett, 2000, 283(3):230-232. DOI: 10.1016/s0304-3940(00)00971-x .
99	YANG D M, KNIGHT R A, HAN Y X, et al. Vascular recovery promoted by atorvastatin and simvastatin after experimental intracerebral hemorrhage: magnetic resonance imaging and histological study[J]. J Neurosurg, 2011, 114(4):1135-1142. DOI: 10.3171/2010.7.JNS10163 .
100	KARKI K, KNIGHT R A, HAN Y X, et al. Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage[J]. Stroke, 2009, 40(10):3384-3389. DOI: 10.1161/STROKEAHA.108.544395 .
101	SINAR E J, MENDELOW A D, GRAHAM D I, et al. Experimental intracerebral hemorrhage: effects of a temporary mass lesion[J]. J Neurosurg, 1987, 66(4):568-576. DOI: 10.3171/jns.1987.66.4.0568 .
102	NAKASHIMA K, YAMASHITA K, UESUGI S, et al. Temporal and spatial profile of apoptotic cell death in transient intracerebral mass lesion of the rat[J]. J Neurotrauma, 1999, 16(2):143-151. DOI: 10.1089/neu.1999.16.143 .
103	REN R, LU Q, SHERCHAN P, et al. Inhibition of aryl hydrocarbon receptor attenuates hyperglycemia-induced hematoma expansion in an intracerebral hemorrhage mouse model [J]. J Am Heart Assoc, 2021, 10(20): e022701. DOI: 10.1161/JAHA.121.022701 .
104	OKAMOTO K, YAMORI Y, NAGAOKA A. Establishment of the stroke-prone spontaneously hypertensive rat (SHR)[J]. Circ Res, 1974, 35: 1143-1153.
105	ZENG J, ZHANG Y, MO J, et al. Two-kidney, two clip renovascular hypertensive rats can be used as stroke-prone rats[J]. Stroke, 1998, 29(8):1708-1713; discussion 1713-1714. DOI: 10.1161/01.str.29.8.1708 .
106	GUO H X, YOU M F, WU J H, et al. Genetics of spontaneous intracerebral hemorrhage: risk and outcome[J]. Front Neurosci, 2022, 16:874962. DOI: 10.3389/fnins.2022.874962 .
107	EKKERT A, ŠLIACHTENKO A, UTKUS A, et al. Intracerebral hemorrhage genetics[J]. Genes, 2022, 13(7):1250. DOI: 10. 3390/genes13071250 .
108	CHARIDIMOU A, BOULOUIS G, GUROL M E, et al. Emerging concepts in sporadic cerebral amyloid angiopathy[J]. Brain, 2017, 140(7):1829-1850. DOI: 10.1093/brain/awx047 .
109	GOKHALE S, CAPLAN L R, JAMES M L. Sex differences in incidence, pathophysiology, and outcome of primary intracerebral hemorrhage[J]. Stroke, 2015, 46(3):886-892. DOI: 10.1161/STROKEAHA.114.007682 .
110	AUER R N, SUTHERLAND G R. Primary intracerebral hemorrhage: pathophysiology[J]. Can J Neurol Sci Le J Can Des Sci Neurol, 2005, 32(): S3-S12.
111	BIFFI A, GREENBERG S M. Cerebral amyloid angiopathy: a systematic review[J]. J Clin Neurol, 2011, 7(1):1-9. DOI: 10.3988/ jcn.2011.7.1.1 .
112	BILKEI-GORZO A. Genetic mouse models of brain ageing and Alzheimer’s disease[J]. Pharmacol Ther, 2014, 142(2):244-257. DOI: 10.1016/j.pharmthera.2013.12.009 .
113	WINKLER D T, BONDOLFI L, HERZIG M C, et al. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy[J]. J Neurosci, 2001, 21(5):1619-1627. DOI: 10.1523/ JNEUROSCI.21-05-01619.2001 .
114	STURCHLER-PIERRAT C, ABRAMOWSKI D, DUKE M, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology[J]. Proc Natl Acad Sci USA, 1997, 94(24):13287-13292. DOI: 10.1073/pnas.94.24.13287 .
115	DAVIS J, XU F, DEANE R, et al. Early-onset and robust cerebral microvascular accumulation of amyloid beta- protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta- protein precursor[J]. J Biol Chem, 2004, 279(19):20296-20306. DOI: 10.1074/jbc.M312946200 .
116	HERZIG M C, WINKLER D T, BURGERMEISTER P, et al. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis[J]. Nat Neurosci, 2004, 7(9):954-960. DOI: 10.1038/nn1302 .
117	MAAT-SCHIEMAN M, ROOS R, VAN DUINEN S. Hereditary cerebral hemorrhage with amyloidosis-Dutch type[J]. Neuropathology, 2005, 25(4):288-297. DOI: 10.1111/j.1440- 1789.2005.00631.x .
118	FISHER M, VASILEVKO V, PASSOS G F, et al. Therapeutic modulation of cerebral microhemorrhage in a mouse model of cerebral amyloid angiopathy[J]. Stroke, 2011, 42(11):3300- 3303. DOI: 10.1161/STROKEAHA.111.626655 .
119	HAN B H, ZHOU M L, JOHNSON A W, et al. Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice[J]. Proc Natl Acad Sci USA, 2015, 112(8): E881- E890. DOI: 10.1073/pnas.1414930112 .
120	COOMARASWAMY J, KILGER E, WÖLFING H, et al. Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer’s disease[J]. Proc Natl Acad Sci USA,2010,107(17):7969-7974.DOI:10.1073/pnas. 1001056107 .
121	VOLLHERBST D F, BENDSZUS M, MÖHLENBRUCH M A. Vascular malformations of the brain and its coverings[J]. J Neuroendovasc Ther, 2020, 14(8):285-294. DOI: 10.5797/jnet. ra.2020-0020 .
122	NARANBHAI N, PÉREZ R. Management of brain arteriovenous malformations: a review[J]. Cureus, 2023, 15(1): e34053. DOI: 10.7759/cureus.34053 .
123	BARBOSA DO PRADO L, HAN C, OH S P, et al. Recent advances in basic research for brain arteriovenous malformation[J]. Int J Mol Sci, 2019, 20(21):5324. DOI: 10.3390/ ijms20215324 .
124	WINKLER E A, PACULT M A, CATAPANO J S, et al. Emerging pathogenic mechanisms in human brain arteriovenous malformations: a contemporary review in the multiomics era [J]. Neurosurg Focus, 2022, 53(1): E2. DOI: 10.3171/2022.4. FOCUS2291 .
125	VETISKA S, WÄLCHLI T, RADOVANOVIC I, et al. Molecular and genetic mechanisms in brain arteriovenous malformations: new insights and future perspectives[J]. Neurosurg Rev, 2022, 45(6):3573-3593. DOI: 10.1007/s10143-022-01883-4 .
126	MILTON I, OUYANG D, ALLEN C J, et al. Age-dependent lethality in novel transgenic mouse models of central nervous system arteriovenous malformations[J]. Stroke, 2012, 43(5):1432-1435. DOI: 10.1161/STROKEAHA.111.647024 .
127	FISH J E, FLORES SUAREZ C P, BOUDREAU E, et al. Somatic gain of KRAS function in the endothelium is sufficient to cause vascular malformations that require MEK but not PI3K signaling[J]. Circ Res, 2020, 127(6):727-743. DOI: 10.1161/ CIRCRESAHA.119.316500 .
128	PARK E S, KIM S, HUANG S N, et al. Selective endothelial hyperactivation of oncogenic KRAS induces brain arteriovenous malformations in mice[J]. Ann Neurol, 2021, 89 (5):926-941. DOI: 10.1002/ana.26059 .
129	CARLSON T R, YAN Y B, WU X Q, et al. Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice[J]. Proc Natl Acad Sci USA, 2005, 102(28):9884-9889. DOI: 10.1073/pnas.0504391102 .
130	SATOMI J, MOUNT R J, TOPORSIAN M, et al. Cerebral vascular abnormalities in a murine model of hereditary hemorrhagic telangiectasia[J]. Stroke, 2003, 34(3):783-789. DOI: 10.1161/01.STR.0000056170.47815.37 .
131	YAO Y C, YAO J Y, RADPARVAR M, et al. Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency[J]. Proc Natl Acad Sci USA, 2013, 110(47):19071-19076. DOI: 10.1073/pnas.1310905110 .
132	NIELSEN C M, CUERVO H, DING V W, et al. Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice[J]. Development, 2014, 141(19):3782-3792. DOI: 10.1242/dev.108951 .
133	SU H, KIM H, PAWLIKOWSKA L, et al. Reduced expression of integrin alphavbeta8 is associated with brain arteriovenous malformation pathogenesis[J]. Am J Pathol, 2010, 176(2):1018- 1027. DOI: 10.2353/ajpath.2010.090453 .
134	MOUCHTOURIS N, CHALOUHI N, CHITALE A, et al. Management of cerebral cavernous malformations: from diagnosis to treatment[J]. Sci World J, 2015, 2015:808314. DOI: 10.1155/2015/808314 .
135	NIKOUBASHMAN O, DI ROCCO F, DAVAGNANAM I, et al. Prospective hemorrhage rates of cerebral cavernous malformations in children and adolescents based on MRI appearance[J]. AJNR Am J Neuroradiol, 2015, 36(11):2177- 2183. DOI: 10.3174/ajnr.A4427 .
136	HOFFMAN J E, WITTENBERG B, MOREL B, et al. Tailored treatment options for cerebral cavernous malformations[J]. J Pers Med, 2022, 12(5):831. DOI: 10.3390/jpm12050831 .
137	WANG Y D, NAKAYAMA M, PITULESCU M E, et al. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis [J]. Nature, 2010, 465(7297):483-486. DOI: 10.1038/ nature09002 .
138	BOULDAY G, RUDINI N, MADDALUNO L, et al. Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice[J]. J Exp Med, 2011, 208(9): 1835-1847. DOI: 10.1084/jem.20110571 .
139	BOULDAY G, BLÉCON A, PETIT N, et al. Tissue-specific conditional CCM2 knockout mice establish the essential role of endothelial CCM2 in angiogenesis: implications for human cerebral cavernous malformations[J]. Dis Model Mech, 2009, 2(3-4):168-177. DOI: 10.1242/dmm.001263 .
140	MCDONALD D A, SHENKAR R, SHI C B, et al. A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease[J]. Hum Mol Genet, 2011, 20(2):211-222. DOI: 10.1093/ hmg/ddq433 .
141	JEANNE M, LABELLE-DUMAIS C, JORGENSEN J, et al. COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke[J]. Am J Hum Genet, 2012, 90 (1):91-101. DOI: 10.1016/j.ajhg.2011.11.022 .
142	WENG Y C, SONNI A, LABELLE-DUMAIS C, et al. COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage[J]. Ann Neurol, 2012, 71(4):470-477. DOI: 10.1002/ ana.22682 .
143	SHAH S, ELLARD S, KNEEN R, et al. Childhood presentation of COL4A1 mutations[J]. Dev Med Child Neurol, 2012, 54(6): 569-574. DOI: 10.1111/j.1469-8749.2011.04198.x .
144	GOULD D B, PHALAN F C, BREEDVELD G J, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly[J]. Science, 2005, 308(5725):1167-1171. DOI: 10.1126/science.1109418 .
145	BEDERSON J B, PITTS L H, TSUJI M, et al. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination[J]. Stroke, 1986, 17 (3):472-476. DOI: 10.1161/01.str.17.3.472 .
146	LONGA E Z, WEINSTEIN P R, CARLSON S, et al. Reversible middle cerebral artery occlusion without craniectomy in rats [J]. Stroke, 1989, 20(1):84-91. DOI: 10.1161/01.str.20.1.84 .
147	FEENEY D M, BOYESON M G, LINN R T, et al. Responses to cortical injury: I. Methodology and local effects of contusions in the rat[J]. Brain Res, 1981, 211(1):67-77. DOI: 10.1016/0006- 8993(81)90067-6 .
148	GARCIA J H, WAGNER S, LIU K F, et al. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation[J]. Stroke, 1995, 26(4):627-634, 635. DOI: 10.1161/01.str.26.4.627 .
149	CHEN J, SANBERG P R, LI Y, et al. Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats[J]. Stroke, 2001, 32(11):2682-2688. DOI: 10.1161/hs1101.098367 .
150	HARTMAN R, LEKIC T, ROJAS H, et al. Assessing functional outcomes following intracerebral hemorrhage in rats [J]. Brain Res,2009,1280:148-157. DOI:10.1016/j.brainres.2009. 05.038 .
151	TOMITA H, ITO U, OHNO K, et al. Chronological changes in brain edema induced by experimental intracerebral hematoma in cats[J]. Acta Neurochir Suppl, 1994, 60:558-560. DOI: 10.1007/978-3-7091-9334-1_154 .
152	LEE E J, HUNG Y C. Marked anemic hypoxia deteriorates cerebral hemodynamics and brain metabolism during massive intracerebral hemorrhage[J]. J Neurol Sci, 2001, 190 (1-2):3-10. DOI: 10.1016/s0022-510x(01)00567-6 .
153	MUN-BRYCE S, WILKERSON A C, PAPUASHVILI N, et al. Recurring episodes of spreading depression are spontaneously elicited by an intracerebral hemorrhage in the swine[J]. Brain Res, 2001, 888(2):248-255. DOI: 10.1016/s0006-8993(00)03068-7 .
154	BULLOCK R, MENDELOW A D, TEASDALE G M, et al. Intracranial haemorrhage induced at arterial pressure in the rat. Part 1: description of technique, ICP changes and neuropathological findings[J]. Neurol Res, 1984, 6(4):184-188. DOI: 10.1080/01616412.1984.11739687 .
155	林潇, 倪浩棋, 黄李洁, 等. 常用脑出血动物模型的研究进展[J]. 温州医科大学学报, 2017, 47(9):698-703. DOI: 10.3969/j. issn.2095-9400.2017.09.017 .
	LIN X, NI H Q, HUANG L J, et al. Research progress of common animal models of cerebral hemorrhage[J]. J Wenzhou Med Univ, 2017, 47(9):698-703. DOI: 10.3969/j. issn.2095-9400.2017.09.017 .
156	胡凌峰, 柳洁, 范胜涛. NHP实验动物在神经科学领域的应用及挑战[J]. 中国比较医学杂志, 2024, 34(1):151-157. DOI:10. 3969 / j. issn.1671-7856. 2024. 01. 020 .
	HU L F, LIU J, FAN S T. Application and challenges of NHP laboratory animals in neuroscience[J]. Chin J Comp Med, 2024, 34(1):151-157. DOI:10. 3969/j.issn.1671-7856.2024.01.020 .
157	宋洋, 付金凤. 浅谈实验用猫的饲养与管理方法[J]. 黑龙江医药, 2011, 24(6):928-930.
	SONG Y, FU J F. A brief discussion on the feeding and management methods of experimental cats[J]. Heilongjiang Med J, 2011, 24(6):928-930.
158	ZHAO H, LIU E Q, ZHANG Y Q. Dog models of human atherosclerotic cardiovascular diseases[J]. Mamm Genome, 2023, 34(2):262-269. DOI: 10.1007/s00335-022-09965-w .
159	TAHA A, BOBI J, DAMMERS R, et al. Comparison of large animal models for acute ischemic stroke: which model to use?[J]. Stroke, 2022, 53(4):1411-1422. DOI: 10.1161/ STROKEAHA.121.036050 .
160	TAYLOR K, ALVAREZ L R. An estimate of the number of animals used for scientific purposes worldwide in 2015[J]. Altern Lab Anim, 2019, 47(5-6):196-213. DOI: 10.1177/ 0261192919899853 .
161	ANDRADE A F, SOARES M S, PATRIOTA G C, et al. Experimental model of intracranial hypertension with continuous multiparametric monitoring in swine[J]. Arq Neuropsiquiatr, 2013, 71(10):802-806. DOI: 10.1590/0004- 282X20130126 .
162	刘智, 袁楠, 兰天野, 等. 脑出血实验动物模型制备及在中医药研究中的应用[J]. 毒理学杂志, 2019, 5 (4):323-326.
	LIU Z, YUAN N, LAN T Y, et al. Preparation of experimental animal models of cerebral hemorrhage and their application in traditional Chinese medicine research[J]. J Toxicol, 2019, 5(4):323-326.
163	KRAFFT P R, ROLLAND W B, DURIS K, et al. Modeling intracerebral hemorrhage in mice: injection of autologous blood or bacterial collagenase[J]. J Vis Exp, 2012(67): e4289. DOI: 10.3791/4289 .
164	LOVE C J, KIRSCHENBAUM D, SELIM M, et al. Observation of collagen-containing lesions after hematoma resolution in intracerebral hemorrhage [J]. Stroke,2021,52(5):1856-1860.DOI:10.1161/STROKEAHA. 120.030240 .
165	XUE M Z, DEL BIGIO M R. Comparison of brain cell death and inflammatory reaction in three models of intracerebral hemorrhage in adult rats[J]. J Stroke Cerebrovasc Dis, 2003, 12(3):152-159. DOI: 10.1016/S1052-3057(03)00036-3 .
166	LASO-GARCIA F, CASADO-FERNANDEZ L, PINIELLA D, et al. Circulating extracellular vesicles promote recovery in a preclinical model of intracerebral hemorrhage[J]. Mol Ther Nucleic Acids, 2023, 32:247-262. DOI: 10.1016/j.omtn.2023. 03.006 .
167	KRAFFT P R, ROLLAND W B, DURIS K, et al. Modeling intracerebral hemorrhage in mice: injection of autologous blood or bacterial collagenase [J]. J Vis Exp, 2012, (67): e4289.DOI:10.3791/4289 .
168	段晓春, 王中, 陈罡. 脑出血动物模型研究进展[J]. 中华神经创伤外科电子杂志, 2015(2):36-39. DOI: 10.3877/cma.j.issn.2095- 9141.2015.02.011 .
	DUAN X C, WANG Z, CHEN G. The research progress of animal model of cerebral hemorrhage[J]. Chin J Neurotraumatic Surg Electron Ed, 2015(2):36-39. DOI: 10.3877/cma.j.issn.2095-9141.2015.02.011 .
169	JING C H, BIAN L H, WANG M, et al. Enhancement of hematoma clearance with CD47 blocking antibody in experimental intracerebral hemorrhage[J]. Stroke, 2019, 50(6): 1539-1547. DOI: 10.1161/STROKEAHA.118.024578 .
170	WAGNER K R, XI G, HUA Y, et al. Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihematomal white matter[J]. Stroke, 1996, 27(3):490-497. DOI: 10.1161/01.str.27.3.490 .
171	KINGMAN T A, MENDELOW A D, GRAHAM D I, et al. Experimental intracerebral mass: description of model, intracranial pressure changes and neuropathology[J]. J Neuropathol Exp Neurol, 1988, 47(2):128-137. DOI: 10.1097/ 00005072-198803000-00005 .
172	LOPEZ VALDES E, HERNANDEZ LAIN A, CALANDRE L, et al. Time window for clinical effectiveness of mass evacuation in a rat balloon model mimicking an intraparenchymatous hematoma[J]. J Neurol Sci, 2000, 174(1):40-46. DOI: 10.1016/ s0022-510x(99)00288-9 .
173	KINGMAN T A, MENDELOW A D, GRAHAM D I, et al. Experimental intracerebral mass: time-related effects on local cerebral blood flow[J]. J Neurosurg, 1987, 67(5):732-738. DOI: 10.3171/jns.1987.67.5.0732 .
174	NEHLS D G, MENDELOW D A, GRAHAM D I, et al. Experimental intracerebral hemorrhage: early removal of a spontaneous mass lesion improves late outcome[J]. Neurosurgery, 1990, 27(5):674-682; discussion 682.
175	ZHENG Y, HU Q, MANAENKO A, et al. 17β-Estradiol attenuates hematoma expansion through estrogen receptor α/silent information regulator 1/nuclear factor-kappa b pathway in hyperglycemic intracerebral hemorrhage mice[J]. Stroke,2015,46(2):485-491.DOI:10.1161/STROKEAHA. 114.006372 .
176	European Medicines Agency. ICH guideline M3 ( R2 ) on non- clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals [EB/OL]. [2023-12-22]. .
177	Food and Drug Administration. Guidance, compliance & regulatory information (Biologics)[EB/OL].[2023-12-22]. .
178	陈奇. 中药药理研究方法学[M]. 2版. 北京: 人民卫生出版社, 2006:30-35.
	CHEN Q. Research methods in pharmacology of Chinese Materia Medica[M]. 2nd. Beijing: People’s Health Publishing House, 2006:30-35.
179	GUPTA D, GUPTA S V, YANG N N. Understanding the routes of administration[M]// PATHAK Y V, ARAÚJO DOS SANTOS M, ZEA L. Handbook of space pharmaceuticals. Cham: Springer International Publishing, 2022: 23-47.
180	张谦, 冀瑞俊, 赵萌, 等. 中国脑血管病临床管理指南(第2版)(节选): 第5章脑出血临床管理[J]. 中国卒中杂志, 2023, 18(9):1014- 1023. DOI: 10.3969/j.issn.1673-5765.2023.09.007 .
	ZHANG Q, JI R J, ZHAO M, et al. Chinese stroke association guidelines for clinical management of cerebrovascular diseases (second edition)(excerpt)—chapter five clinical management of intracerebral hemorrhage[J]. Chin J Stroke, 2023, 18(9):1014-1023. DOI: 10.3969/j.issn.1673-5765. 2023. 09.007 .
181	国家卫生计生委脑卒中筛查与防治工程委员会. 脑卒中筛查与防治技术规范[J]. 中国医学前沿杂志(电子版), 2013, 5(9):44-50. DOI: 10.3969/j.issn.1674-7372.2013.09.017 .
	Stroke Screening and Prevention Project Committee, National Health and Family Planning Commissionm, P. R. China. Technical specification for screening and prevention of stroke[J]. Chin J Front Med Sci Electron Version, 2013, 5(9): 44-50. DOI: 10.3969/j.issn.1674-7372.2013.09.017
182	徐叔云. 药理实验方法学[M]. 3版. 北京: 人民卫生出版社, 2002: 200-202.
	XU S Y. Experimental methodology of pharmacology[M]. 3rd. Beijing: People’s Health Publishing House, 2002:200-202.
183	国家市场监督管理总局. 药品注册管理办法[A/OL]. (2020-01- 22)[2024-01-11]. .
	State Administration for Market Regulation. Provisions for drug registration[A/OL]. (2020-01-22)[2024-01-11]. .
184	国家质量监督检验检疫总局, 中国国家标准化管理委员会. 实验动物福利伦理审查指南: GB/T 35892—2018[S]. 北京: 中国标准出版社, 2018
	General Administration of Quality Supervision, Inspection and Quarantine, China National Standardization Commission. Laboratory animal—Guideline for ethical review of animal welfare: GB/T 35892-2018 [S]. Beijing: China Standards Press, 2018.
185	陈佳琦, 吕龙宝, 张飞燕, 等. 浅谈微量采血法在药物非临床研究中的应用及3R原则的贯彻[J]. 实验动物与比较医学, 2022, 42(4): 306-312. DOI: 10.12300/j.issn.1674-5817.2021.163 .
	CHEN J Q, LÜ L B, ZHANG F Y, et al. Application of blood microsampling and its implementation of the 3Rs in non-clinical studies of drugs[J]. Lab Anim Comp Med, 2022, 42(4): 306-312. DOI: 10.12300/j.issn.1674-5817.2021.163 .

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