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中华脑血管病杂志(电子版) ›› 2021, Vol. 15 ›› Issue (02) : 64 -69. doi: 10.11817/j.issn.1673-9248.2021.02.001

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自发性脑出血动物模型的研究进展
张钦1, 杨清武1,()   
  1. 1. 400037 重庆,中国人民解放军陆军军医大学(原第三军医大学)第二附属医院(新桥医院)神经内科
  • 收稿日期:2020-12-29 出版日期:2021-04-01
  • 通信作者: 杨清武
  • 基金资助:
    重庆市自然科学基金创新群体科学基金,卒中后脑高级功能障碍的神经环路解析的基础研究(cstc2019jcyj-cxttX0005)

The advances in animal models of spontaneous intracerebral hemorrhage

Qin Zhang1, Qingwu Yang1,()   

  1. 1. Department of Neurology, Second Affiliated Hospital (Xinqiao Hospital), the Army Medical University (Third Military Medical University), Chongqing 400037, China
  • Received:2020-12-29 Published:2021-04-01
  • Corresponding author: Qingwu Yang
引用本文:

张钦, 杨清武. 自发性脑出血动物模型的研究进展[J]. 中华脑血管病杂志(电子版), 2021, 15(02): 64-69.

Qin Zhang, Qingwu Yang. The advances in animal models of spontaneous intracerebral hemorrhage[J]. Chinese Journal of Cerebrovascular Diseases(Electronic Edition), 2021, 15(02): 64-69.

脑出血是致死致残率最高的脑卒中类型,至今仍无明确有效的治疗手段。缺乏与脑出血临床特征相契合的动物模型可能是阻碍其研究的根本原因。本文通过回顾现有自发性脑出血小鼠模型,共发现2种高血压脑出血模型、1种自发性深部脑出血模型和5种脑淀粉样血管病模型。高血压模型其中一种是双转基因小鼠,通过过表达人肾素和血管紧张素原,导致小鼠高血压。然而,该模型脑出血的发生需要结合高盐饮食和一氧化氮合酶抑制剂。另一种则采用皮下缓慢释放血管紧张素Ⅱ和抑制一氧化氮合酶导致慢性高血压,随后急性注射血管紧张素Ⅱ进一步提升血压造成血压剧烈波动诱导脑出血发生。自发性深部脑出血模型可能是除高血压因素外研究深部脑出血最理想的小鼠模型。5种淀粉样血管病模型均建立在淀粉样前体蛋白突变型的转基因小鼠,但关于其脑出血特征的研究比较匮乏。目前自发性脑出血仍缺少公认的广泛使用的动物模型,理想的脑出血模型应能最大限度模拟疾病的发展特征,只有开展符合临床实际需要的脑出血基础研究,才有望为脑出血防治提供新的有效靶点。

Intracerebral hemorrhage (ICH) is the type of stroke with the highest mortality and disability. There is still no effective treatment. The scarcity of animal models that strictly simulate the clinical characteristics of ICH may be the root cause for hindering the research of ICH. This article reviews the existing spontaneous ICH mouse models and found two hypertensive ICH models,one spontaneous deep ICH model and five cerebral amyloid angiopathy models. One of the hypertensive models was double transgenic mice,which overexpressed human renin and angiotensinogen,leading to hypertension in mice. However,the occurrence of this model of ICH required a combination of a high-salt diet and a nitric oxide synthase inhibitor. The other hypertensive model utilized slow subcutaneous release of angiotensin Ⅱ and inhibition of nitric oxide synthase to cause chronic hypertension,followed by acute injection of angiotensin Ⅱ to further increase blood pressure and cause dramatic fluctuations in blood pressure to induce ICH. The spontaneous deep ICH model may be the most ideal mouse model for studying ICH except for hypertension. In addition,the five cerebral amyloid angiopathy models were all established in transgenic mice with amyloid precursor protein mutations,but the research on the characteristics of ICH was relatively scarce. At present,spontaneous ICH still lacks widely recognized and used animal models. The ideal ICH model should be able to simulate the development characteristics of the disease to the greatest extent. Only by carrying out ICH basic research that meets clinical needs can it be expected to provide new and effective targets on ICH prevention and treatment.

23
Iida S, Baumbach GL, Lavoie JL, et al. Spontaneous stroke in a genetic model of hypertension in mice [J]. Stroke, 2005, 36(6): 1253-1258.
24
Wakisaka Y, Miller JD, Chu Y, et al. Oxidative stress through activation of NAD(P)H oxidase in hypertensive mice with spontaneous intracranial hemorrhage [J]. J Cereb Blood Flow Metab, 2008, 28(6): 1175-1185.
25
Wakisaka Y, Chu Y, Miller JD, et al. Spontaneous intracerebral hemorrhage during acute and chronic hypertension in mice [J]. J Cereb Blood Flow Metab, 2010, 30(1): 56-69.
26
Wakisaka Y, Chu Y, Miller JD, et al. Critical role for copper/zincsuperoxide dismutase in preventing spontaneous intracerebral hemorrhage during acute and chronic hypertension in mice [J]. Stroke, 2010, 41(4): 790-797.
27
Ratelade J, Mezouar N, Domenga-Denier V, et al. Severity of arterial defects in the retina correlates with the burden of intracerebral haemorrhage in COL4A1-related stroke [J]. J Pathol, 2018, 244(4): 408-420.
28
Kuo DS, Labelle-Dumais C, Gould DB. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets [J]. Hum Mol Genet, 2012, 21(R1): R97-R110.
29
Jeanne M, Jorgensen J, Gould DB. 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.
30
Exley C, Esiri MM. Severe cerebral congophilic angiopathy coincident with increased brain aluminium in a resident of Camelford, Cornwall, UK [J]. J Neurol Neurosurg Psychiatry, 2006, 77(7): 877-879.
31
Revesz T, Holton JL, Lashley T, et al. Sporadic and familial cerebral amyloid angiopathies [J]. Brain Pathol, 2002, 12(3): 343-357.
32
Jellinger KA. Alzheimer disease and cerebrovascular pathology: an update [J]. J Neural Transm, 2002, 109(5-6): 813-836.
33
Biffi A, Greenberg SM. Cerebral amyloid angiopathy: a systematic review [J]. J Clin Neurol, 2011, 7(1): 1-9.
34
Rosand J, Muzikansky A, Kumar A, et al. Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy [J]. Ann Neurol, 2005, 58(3): 459-462.
35
Vinters HV. Cerebral amyloid angiopathy. A critical review [J]. Stroke, 1987,18(2): 311-324.
36
Braunmuhl AV. Senile vascular necrosis [J]. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr, 1950, 185(5): 571-583.
37
Walker LC. Animal models of cerebral β-amyloid angiopathy [J]. Brain Res Brain Res Rev, 1997, 25(1): 70-84.
38
Elfenbein HA, Rosen RF, Stephens SL, et al. Cerebral beta-amyloid angiopathy in aged squirrel monkeys [J]. Histol Histopathol, 2007, 22(2): 155-167.
39
Bilkei-Gorzo A. Genetic mouse models of brain ageing and Alzheimer's disease [J]. Pharmacol Ther, 2014, 142(2): 244-257.
40
Winkler DT, Bondolfi L, Herzig MC, et al. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy [J]. J Neurosci, 2001, 21(5): 1619-1627.
41
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): 13287-1392.
42
Davis J, Xu F, Deane R, et al. Early-onset and robust cerebral microvascular accumulation of amyloid β-protein in transgenic mice expressing low levels of a vasculotropic dutch/iowa mutant form of amyloid β-protein precursor [J]. J Biol Chem, 2004, 279(19): 20296-20306.
43
Herzig MC, Winkler DT, Burgermeister P, et al. Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis [J]. Nat Neurosci, 2004, 7(9): 954-960.
44
Fisher M, Vasilevko V, Passos GF, et al. Therapeutic modulation of cerebral microhemorrhage in a mouse model of cerebral amyloid angiopathy [J]. Stroke, 2011, 42(11): 3300-3303.
45
Coomaraswamy J, Kilger E, Wolfing 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.
1
Liu M, Wu B, Wang WZ, et al. Stroke in China: epidemiology, prevention, and management strategies [J]. Lancet Neurol, 2007, 6(5): 456-464.
2
van Asch CJ, Luitse MJ, Rinkel GJ, 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.
3
杨清武. 脑出血临床防治困惑及转化研究新策略 [J]. 中华医学信息导报, 2017, 32(17): 21.
4
Foulkes MA, Wolf PA, Price TR, et al. The stroke data bank: design, methods, and baseline characteristics [J]. Stroke, 1988, 195(5): 547-554.
5
Ariesen MJ, Claus SP, Rinkel GJ, et al. Risk factors for intracerebral hemorrhage in the general population: a systematic review [J]. Stroke, 2003, 34(8): 2060-2065.
6
Feldmann E, Broderick JP, Kernan WN, et al. Major risk factors for intracerebral hemorrhage in the young are modifiable [J]. Stroke, 2005, 36(9): 1881-1885.
7
Zia E, Hedblad B, Pessah-Rasmussen H, et al. Blood pressure in relation to the incidence of cerebral infarction and intracerebral hemorrhage: hypertensive hemorrhage: debated nomenclature is still relevant [J]. Stroke, 2007, 38(10): 2681-2685.
8
Nago N, Ishikawa S, Goto T, et al. Low cholesterol is associated with mortality from stroke, heart disease, and cancer: the Jichi Medical School Cohort Study [J]. J Epidemiol, 2011, 21(1): 67-74.
9
Tirschwell DL, Smith NL, Heckbert SR, et al. Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups [J]. Neurology, 2004, 63(10): 1868-1875.
10
Wang QT, Tuhrim S. Etiologies of intracerebral hematomas [J]. Curr Atheroscler Rep, 2012, 14(4): 314-321.
11
Flaherty ML. Anticoagulant-associated intracerebral hemorrhage [J]. Semin Neurol, 2010, 30(5): 565-572.
12
Greenberg MS. Handbook of Neurosurgery [M]. 8 editon. USA: Thieme Publishers, 2016, 87: 1331-1332.
13
Prayson RA. Neuropatholog [M]. 2 editon. USA: Elsevier Health Sciences, 2012, 2: 49-50.
14
Auer RN, Sutherland GR. Primary intracerebral hemorrhage: pathophysiology [J]. Can J Neurol Sci, 2005, 32(Suppl 2): S3-S12.
15
Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage [J]. Lancet, 2009, 373(9675): 1632-1644.
16
Aguilar MI, Freeman WD. Spontaneous intracerebral hemorrhage [J]. Semin Neurol, 2010, 30(5): 555-564.
17
O'Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage [J]. N Engl J Med, 2000, 342(4): 240-245.
18
Woo D, Broderick JP. Spontaneous intracerebral hemorrhage: epidemiology and clinical presentation [J]. Neurosurg Clin N Am, 2002, 13(3): 265-279.
19
Klebe D, Iniaghe L, Burchell S, et al. Intracerebral hemorrhage in mice [J]. Methods Mol Biol, 2018, 1717: 83-91.
20
Merrill DC, Thompson MW, Carney CL, et al. Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes [J]. J Clin Invest, 1996, 97(4): 1047-1055.
21
Smeda JS. Hemorrhagic stroke development in spontaneously hypertensive rats fed a North American, Japanese-style diet [J]. Stroke, 1989, 20(9): 1212-1218.
22
Ahmad S. Angiotensin receptor antagonists delay nitric oxide-deficient stroke in stroke-prone rats [J]. Eur J Pharmacol, 1997, 333(1): 39-45.
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