Abstract
BackgroundAnimal models are essential to study the pathophysiological changes associated with focal occlusive stroke and to investigate novel therapies. Currently used rodent models have yielded little clinical success, however large animal models may provide a more suitable alternative to improve clinical translation. We sought to develop a model of acute proximal middle cerebral artery (MCA) ischemic stroke in sheep, including both permanent occlusion and transient occlusion with reperfusion.Materials and Methods18 adult male and female Merino sheep were randomly allocated to one of three groups (n = 6/gp): 1) sham surgery; 2) permanent proximal MCA occlusion (MCAO); or 3) temporary MCAO with aneurysm clip. All animals had invasive arterial blood pressure, intracranial pressure and brain tissue oxygen monitoring. At 4 h following vessel occlusion or sham surgery animals were killed by perfusion fixation. Brains were processed for histopathological examination and infarct area determination. 6 further animals were randomized to either permanent (n = 3) or temporary MCAO (n = 3) and then had magnetic resonance imaging (MRI) at 4 h after MCAO.ResultsEvidence of ischemic injury in an MCA distribution was seen in all stroke animals. The ischemic lesion area was significantly larger after permanent (28.8%) compared with temporary MCAO (14.6%). Sham animals demonstrated no evidence of ischemic injury. There was a significant reduction in brain tissue oxygen partial pressure after permanent vessel occlusion between 30 and 210 mins after MCAO. MRI at 4 h demonstrated complete proximal MCA occlusion in the permanent MCAO animals with a diffusion deficit involving the whole right MCA territory, whereas temporary MCAO animals demonstrated MRA evidence of flow within the right MCA and smaller predominantly cortical diffusion deficits.ConclusionsProximal MCAO can be achieved in an ovine model of stroke via a surgical approach. Permanent occlusion creates larger infarct volumes, however aneurysm clip application allows for reperfusion.
Highlights
The current clinical treatment of acute occlusive middle cerebral artery (MCA) stroke is directed towards early reperfusion of the ischemic brain in a timely fashion by thrombolysis or thrombectomy [1,2]
There was a significant reduction in brain tissue oxygen partial pressure after permanent vessel occlusion between 30 and 210 mins after MCA occlusion (MCAO)
Proximal MCAO can be achieved in an ovine model of stroke via a surgical approach
Summary
The current clinical treatment of acute occlusive middle cerebral artery (MCA) stroke is directed towards early reperfusion of the ischemic brain in a timely fashion by thrombolysis or thrombectomy [1,2]. Over 1000 agents have shown to be efficacious in preclinical evaluation, with only tissue plasminogen activator translating into a successful clinical therapy [6,7,8] This poor translation has led many researchers to believe that rodent models have limited predictive value and that alternate large animal models are likely to become important in future translational research [9,10]. An ovine model of permanent focal cerebral ischemia has recently been developed to capitalize on the advantages of large animal translation [12], this model offers only permanent vessel occlusion and the technique of MCA exposure and occlusion was only briefly described. We sought to develop a model of acute proximal middle cerebral artery (MCA) ischemic stroke in sheep, including both permanent occlusion and transient occlusion with reperfusion
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