Animal Models of Stroke
Overview of Stroke
The brain, as the general headquarters of the entire nervous system and the whole human body, once its structure or function is affected, will cause a series of disorders. Stroke is a severe condition in which the focal neurological deficit is caused by alterations in the cerebral circulation. It is one of the health concerns all over the world with high mortality and disability rate. Stroke is generally divided into hemorrhagic stroke (caused by cerebral hemorrhage) and ischemic stroke (caused by cerebral infarction or thrombus) according to the specific etiology. Hypertension, atherosclerosis, cardiovascular disease, cerebral embolism, intracranial tumor, etc., all are possible risk factors for stroke.
Ischemic stroke is the primary type among the two types, affecting around 85% of stroke patients, which is caused by partial cerebral supply loss leading to ischemic cascades. Atherosclerosis or blood clots in the vessel can deposit in the blood vessels of the brain, resulting in blood flow reduction, disruption of blood supply balance, and even embolic infarction. Partial blood vessels in the brain are blocked, and the blood flowing to the brain is reduced, causing local hypoxia and anaerobic metabolism, as well as increased local pressure and cell necrosis. The release of anaerobic metabolites and necrotic cell contents all negatively affect the function of surrounding neurons by the ways of acidosis, inflammation, abnormal intracellular calcium levels, oxidative stress, glutamate excitotoxicity, and so forth.
Fig.1 Major cellular pathophysiological mechanisms of ischemic stroke. (Woodruff, 2011)
Animal Models of Stroke
To identify precise mechanisms and discover new treatments for stroke, a variety of animal stroke models, including global or focal ischemia models, in vitro or in vivo stroke models, induced or spontaneous models, have been developed over the past few decades. Here we list some typical animal models of stroke.
Fig.2 Various animal models of ischemia and stroke.
- Intraluminal suture MCAo model
- Craniectomy model
- The Levine-Rice model
- Photo-thrombosis stoke model
- Endothelin 1 vasoconstriction modeling
This model is established by inserting a suture to block the carotid artery in mice or rats until the blood flow of the middle cerebral artery (MCA) was blocked. The MCAo model, commonly in C57BL/6 and SV129 mice, can well replicate ischemic stroke and related clinical representations, such as cerebral inflammation, neuronal cell death, and blood-brain barrier injury.
Stroke animals can be directly modeled by inducing occlusion in the artery through a surgical procedure. After exposure of MCA by craniotomy and dural incision, reduction or interruption of local blood flow and impairment of neurological function can be caused by electrocoagulation or three-vessel occlusion in mice. This approach for stroke modeling is advantageous in low mortality and good reproducibility in infarct size and neurologic deficits.
This Levine-Rice model has been extensively applied for the investigation of neonatal hypoxic-ischemic stroke and human perinatal ischemic stroke. Unilateral common carotid artery rat pups were ligated, followed by reperfusion and recovery. Subsequently, the rats are exposed to hypoxia to explore the pathophysiological mechanism of neonatal stroke.
This is a thromboischemia mouse model with advantages of high reproducibility, low mortality, and no surgery. After intraperitoneal administration of photoreactive dyes, the whole skull will be irradiated with a specific wavelength of a light beam, which leads to photo-oxidation of reactive dyes in blood vessels, resulting in vascular endothelial injury, blood vessel aggregation in the brain parenchyma, and platelet stimulation.
Specifical injection of Endothelin 1, a small vasoactive peptide acting to restrict the vascular system through cell-specific receptors, to the exposed MCA in the intracerebral or cortex region, inducing ischemic lesion. This modeling approach is minimally invasive with low mortality, which is the size of the lesion can be controlled by adjusting the concentration of ET-1, making it suitable for long-term lesion research.
Table.1 Advantages and disadvantages of the stroke models. (Kuriakose, 2020)
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References
- Woodruff, T.M.; et al. Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Molecular Neurodegeneration. 2011, 6: 11.
- Kuriakose, D.; Xiao, Z.C. Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives. International Journal of Molecular Sciences. 2020, 21(20): 7609.
