Ischemic stroke: experimental models and reality

Abstract

The vast majority of cerebral stroke cases are caused by transient or permanent occlusion of a cerebral blood vessel ("ischemic stroke") eventually leading to brain infarction. The final infarct size and the neurological outcome depend on a multitude of factors such as the duration and severity of ischemia, the existence of collateral systems and an adequate systemic blood pressure, etiology and localization of the infarct, but also on age, sex, comorbidities with the respective multimedication and genetic background. Thus, ischemic stroke is a highly complex and heterogeneous disorder. It is immediately obvious that experimental models of stroke can cover only individual specific aspects of this multifaceted disease. A basic understanding of the principal molecular pathways induced by ischemia-like conditions comes already from in vitro studies. One of the most frequently used in vivo models in stroke research is the endovascular suture or filament model in rodents with occlusion of the middle cerebral artery (MCA), which causes reproducible infarcts in the MCA territory. It does not require craniectomy and allows reperfusion by withdrawal of the occluding filament. Although promptly restored blood flow is far from the pathophysiology of spontaneous human stroke, it more closely mimics the therapeutic situation of mechanical thrombectomy which is expected to be increasingly applied to stroke patients. Direct transient or permanent occlusion of cerebral arteries represents an alternative approach but requires craniectomy. Application of endothelin-1, a potent vasoconstrictor, allows induction of transient focal ischemia in nearly any brain region and is frequently used to model lacunar stroke. Circumscribed and highly reproducible cortical lesions are characteristic of photothrombotic stroke where infarcts are induced by photoactivation of a systemically given dye through the intact skull. The major shortcoming of this model is near complete lack of a penumbra. The two models mimicking human stroke most closely are various embolic stroke models and spontaneous stroke models. Closeness to reality has its price and goes along with higher variability of infarct size and location as well as unpredictable stroke onset in spontaneous models versus unpredictable reperfusion in embolic clot models.

Keywords: Animal model; Cerebral ischemia; Focal ischemia; In vitro model; Non-human primate; Stroke.

Fig. 1

Illustration of connectivity as obtained by 3D-polarized light imaging (3D-PLI) [5, 6, 139]. Coronal sections from a human brain, a vervet (monkey) and a rat brain. The color sphere indicates the direction of fibers; black corresponds to a steep course of fibers in the third dimension, within the physical section. The comparison illustrates that not only the absolute volume of brains differs among the three species, but also the relative amount with a much higher proportion of white matter in human brains as compared to vervet and rodent brains. (Images by courtesy of Markus Axer, Karl Zilles and Katrin Amunts, Forschungszentrum Jülich, Germany)

Fig. 2

Imaging of the human (a) and murine cerebrovascular system (b). Although the principle plan of cerebrovascular organization is similar in humans (a) and mice (b), some differences exist. The BA, for example, in humans most often terminates by splitting into the PCA, whereas in mice the BA in most cases terminates by splitting into the SCA (with the PCA originating from the ICA). Also, in humans the postcommunicating ACAs normally are paired, whereas mice feature an azygos ACA. a Time-of-flight MR angiography showing the human arterial cerebrovascular system, (maximum intensity projection, AP view); b in vivo digital subtraction angiography (DSA) of the murine cerebrovascular system [35, 111]. Images courtesy of Prof. Marc A. Brockmann, Department of Neuroradiology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. ACA anterior cerebral artery, BA basilar artery, ICA internal carotid artery, MCA middle cerebral artery, PCA posterior cerebral artery, SCA superior cerebellar artery, VA vertebral artery

Fig. 3

Media infarcts in human (a, c) and rat brain (b). An acute ischemic stroke in the territory of the middle cerebral artery (MCA) in a human brain (a; asterisk infarct). Such acute large media infarcts are easily modeled with the filament technique (b; rat, 120 min transient ischemia, 24 h survival; TTC stain: vital tissue red, white tissue (asterisk) indicates infarct; inset: real proportions of the rat brain compared to human brain. Chronic infarcts (c, human) of similar sizes in rodents rarely come to examination