Focal Ischemic Stroke Models

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Various stroke models have been developed in the past 20 years.8 However, those in use today include the unilateral middle cerebral artery occlusion (MCAO) model used in rats and mice. Since these models were first developed in the 1980s, the MCAO has been variably induced by surgical ligation or cauterization via a small craniotomy over the middle cerebral artery, passage of a intraluminal nylon suture up into the ipsilateral cerebral circulation via the external carotid in the neck, or injection of a small autologous thrombus into the common carotid artery. The latter two methods are the most commonly employed today, and the thromboembolic paradigm is the most clinically relevant, since the majority of human focal ischemic strokes involve a thromboembolic occlusion of the middle cerebral artery. The MCAO models come in two varieties: temporary and permanent. The temporary MCAO involves removal of the vascular occlusion at varying times (30, 60, 90, 120, 180 min) after the onset in order to allow reperfusion of the ischemic tissue to take place. This experimental scenario, which is accomplished by surgical removal of the extraluminal or intraluminal occlusion device, mimics either the instance where spontaneous thrombus dissolution may take place during the first 3 h after the beginning of the stroke due to the activation of endogenous thrombolytic processes (believed to be a fairly rare occurrence), or the situation where the stroke victim is treated with the thrombolytic agent tissue plasminogen activator (TPA) for the purpose of dissolving the clot and restoring recirculation. Although removal of the vascular occlusion and re-establishment of the normal cerebral circulation is an obviously desirable therapeutic goal, it is a double-edged sword that can lead to 'reperfusion injury', which is caused by a burst of ROS in the previously ischemic brain tissue. Thus, there is a need in this situation for a neuroprotective agent, to reduce both the pathophysiological events set in motion by the ischemic insult and the subsequent deleterious side effects of pharmacological recirculation. Accordingly, the temporary MCAO models are most useful for evaluating neuroprotective strategies that may be used in conjunction with TPA and other thrombolytic agents. However, since pharmacological thrombolysis can lead to secondary cerebral hemorrhage if used beyond the first few hours, it can only be safely employed in patients who are available for emergency treatment during the first few hours after the onset of their strokes. This is only feasible in a small fraction of ischemic stroke patients. Furthermore, MCAO animal studies have shown that reperfusion beyond the first 3 h cannot lessen the extent of ischemic damage. Thus, the temporary MCAO models, although widely used in stroke research, actually have limited relevance to the majority of middle cerebral artery territory strokes.

The second variety of focal ischemic stroke model, the permanent MCAO, where the occlusion is permanently left in place, is therefore a better model of the vast majority of strokes, where recirculation has not been re-established either spontaneously or pharmacologically during the critical first few hours after stroke onset. In this instance, the therapeutic goal is simply to try to reduce the expansion of the ischemic damage from the severely ischemic 'core' area, which is doomed to infarction if reperfusion does not occur during the first 3 h, into the surrounding 'penumbral' area. The 'ischemic penumbra' is potentially salvageable for several hours due to its partial circulation from collateral blood vessels. In the author's opinion, the permanent MCAO version is the best option for preclinical evaluation of potential neuroprotective agents, since it is more relevant to the overall focal ischemic stroke population where early reperfusion is not that common. However, the testing of new compound entities in the temporary MCAO paradigm is also recommended, but not as the only model. Historically, there has been an unfortunate affinity for the temporary models among stroke therapeutic investigators due to the observation that it is generally easier to demonstrate infarct reductions with new compound entities.

Most stroke research with either the temporary or permanent MCAO models is carried out in mice or rats. The primary endpoints are histological demonstration of a reduction in brain infarct size and improvement in motor

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