Abstract
BackgroundIschemic brain injury due to stroke and/or cardiac arrest is a major health issue in modern society requiring urgent development of new effective therapies. The aim of this study was to evaluate mitochondrial, microcirculatory, and histological changes in a swine model of global cerebral ischemia.ResultsIn our model, significant microcirculatory changes, but only negligible histological cell alterations, were observed 3 h after bilateral carotid occlusion, and were more pronounced if the vascular occlusion was combined with systemic hypotension. Analysis of mitochondrial function showed that LEAK respiration (measured in the presence of pyruvate + malate but without ADP) was not affected in any model of global cerebral ischemia in pigs. The OXPHOS capacity with pyruvate + malate as substrates decreased compared with the control levels after bilateral carotid artery occlusion, and bilateral carotid artery occlusion + hypotension by 20% and 79%, respectively, resulting in decreases in the respiratory control index of 14% and 73%, respectively. OXPHOS capacity with succinate as a substrate remained constant after unilateral carotid artery occlusion or bilateral carotid artery occlusion, but decreased by 53% after bilateral carotid artery occlusion and hypotension compared with controls (p < 0.05, n = 3–6). Addition of exogenous cytochrome c to mitochondria isolated from ischemia brains had no effect on respiration in all models used in this study.ConclusionsWe found a decrease in microcirculation and mitochondrial oxidative phosphorylation activity, but insignificant neuronal death, after 3 h ischemia in all our pig models of global cerebral ischemia. Dysfunction of the mitochondrial oxidative phosphorylation system, particularly damage to complex I of the respiratory chain, may be the primary target of the ischemic insult, and occurs before signs of neuronal death can be detected.
Highlights
Ischemic brain injury due to stroke and/or cardiac arrest is a major health issue in modern society requiring urgent development of new effective therapies
A significant decrease in mean arterial pressure (MAP) by approximately 50% and an increase in HR by approximately 25% were observed in the bilateral carotid occlusion with systemic hypotension (BCOH) group when compared with baseline and the control group (Table 1)
Our three experimental models of cerebral ischemia in pigs are reliable and useful tools to investigate the mechanism of cerebral ischemia and neuroprotection
Summary
Ischemic brain injury due to stroke and/or cardiac arrest is a major health issue in modern society requiring urgent development of new effective therapies. A number of studies have suggested that occlusion of both common carotid arteries combined with induction of hypotension or hypoxia for a limited time can induce brain ischemia similar to that observed during cardiac arrest and/or massive ischemic stroke [11]. Such studies of brain ischemia in pigs provide little or no data on the exact location and severity of brain gray matter injury. There are no studies demonstrating alterations of microcirculation using direct Sidestream Dark Field (SDF) imaging or changes of mitochondrial respiration in the brain of these experimental models
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