Microcirculatory, mitochondrial, and histological changes following cerebral ischemia in swine

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.

Is chronic curcumin supplementation neuroprotective against ischemia for antioxidant activity, neurologic deficit score, or neuronal apoptosis in an experimental stroke model?

“…While neurological deficits were clearly evident in the ischemic group in our study, the histologic changes were less obvious. In fact, a study that confirmed our findings reported insignificant neuronal death despite reduced mitochondrial oxidative phosphorylation and microcirculation after global ischemia induced by 3-hour BCCAO occlusion (22). Fortunately, we evaluated cell death with TUNEL and detected apoptotic cells.…”

Mitochondrial bioenergetic alterations after focal traumatic brain injury in the immature brain

“…Complex I-driven respiratory dysfunction is a persistent characteristic of early mitochondrial dysfunction within 6–8 h following traumatic and ischemic injury in the brain, and even in other organ systems such as the heart (Almeida et al, 1995; Gilmer et al, 2009; Kunz et al, 2000; Lemieux et al, 2011; Niatsetskaya et al, 2012; Robertson, 2004; Singh et al, 2006; Suchadolskiene et al, 2014). Previous studies in focal TBI, in both mature and immature rodents, have shown a recovery of complex I-driven respiration to sham levels by 24 h post-CCI in the ipsilateral brain, an observation that differs from those in our study (Kilbaugh et al, 2011; Singh et al, 2006).…”

Modern Methods of Perinatal Hypoxic-Ischemic Brain Injury Modeling in Vivo

“…На осно-ве этой модели изучены последствия острого кратко-временного прекращения кровообращения в головном мозге, особенности поведенческих реакций и невроло-гических расстройств животных в ранний и поздний вос-становительный период, а также эффекты длительной гипоксии (более 8 мин) [18]. Несколько позднее техни-ка накладывания манжеты на шею с модификациями (артериальная гипотензия) использовалась на приматах [19] и свиньях [20]. В целом эта модель лучше всего подходит для изучения особенностей нарушения кро-вообращения в гиппокампе и стволе головного мозга.…”

“…Двухсосудистая окклюзия с гипотензией оптималь-но подходит для изучения последствий перенесенной гипоксии-ишемии, эффекта реперфузии, особенностей восстановительного периода. С использованием этой модели изучены особенности фосфолипидного и энерге-тического метаболизма, действия нейротрансмиттеров, морфологические изменения вследствие ишемии, влия-ние различных температурных режимов на исходы пери-натального гипоксически-ишемического поражения ЦНС [20,56]. Сложность определяется необходимостью точного контроля системного артериального давления, длительности ишемии, температуры тела, использова-ния определенного режима анестезии, а также над-лежащего послеоперационного ухода.…”