Cerebral Vascular Disease Research Laboratories, University of Miami School of Medicine, 1420 NW 9th Ave, NRB/203E, Miami, FL, 33136, USA.
Department of Neurology, University of Miami School of Medicine, Miami, FL, 33136, USA.
Transl Stroke Res. 2019 Feb;10(1):78-90. doi: 10.1007/s12975-018-0622-2. Epub 2018 Mar 22.
Diabetes significantly increases the risk of stroke and post-stroke mortality. Recurrent hypoglycemia (RH) is common among diabetes patients owing to glucose-lowering therapies. Earlier, we showed that RH in a rat model of insulin-dependent diabetes exacerbates cerebral ischemic damage. Impaired mitochondrial function has been implicated as a central player in the development of cerebral ischemic damage. Hypoglycemia is also known to affect mitochondrial functioning. The present study tested the hypothesis that prior exposure of insulin-treated diabetic (ITD) rats to RH exacerbates brain damage via enhanced post-ischemic mitochondrial dysfunction. In a rat model of streptozotocin-induced diabetes, we evaluated post-ischemic mitochondrial function in RH-exposed ITD rats. Rats were exposed to five episodes of moderate hypoglycemia prior to the induction of cerebral ischemia. We also evaluated the impact of RH, both alone and in combination with cerebral ischemia, on cognitive function using the Barnes circular platform maze test. We observed that RH exposure to ITD rats leads to increased cerebral ischemic damage and decreased mitochondrial complex I activity. Exposure of ITD rats to RH impaired spatial learning and memory. Our results demonstrate that RH exposure to ITD rats potentially increases post-ischemic damage via enhanced post-ischemic mitochondrial dysfunction.
糖尿病显著增加中风和中风后死亡率的风险。由于降糖治疗，糖尿病患者经常出现反复性低血糖（RH）。早些时候，我们发现胰岛素依赖性糖尿病大鼠模型中的 RH 会加重脑缺血损伤。受损的线粒体功能已被认为是导致脑缺血损伤的核心因素之一。低血糖也已知会影响线粒体功能。本研究通过增强缺血后线粒体功能障碍，检验了先前暴露于 RH 的胰岛素治疗糖尿病（ITD）大鼠是否会通过加重脑损伤来测试假设。在链脲佐菌素诱导的糖尿病大鼠模型中，我们评估了 RH 暴露的 ITD 大鼠的缺血后线粒体功能。在诱导脑缺血之前，大鼠经历了五次中度低血糖发作。我们还使用 Barnes 圆形平台迷宫测试评估了 RH 单独和与脑缺血结合对认知功能的影响。我们观察到 RH 暴露于 ITD 大鼠会导致脑缺血损伤增加和线粒体复合物 I 活性降低。ITD 大鼠暴露于 RH 会损害空间学习和记忆。我们的结果表明，RH 暴露于 ITD 大鼠可能会通过增强缺血后线粒体功能障碍来增加缺血后损伤。
