Department of Neurology, Fourth Military Medical University, Xi'an, China.
Crit Care Med. 2012 Sep;40(9):2685-93. doi: 10.1097/CCM.0b013e318258fb90.
Anesthetic preconditioning appears to be a viable strategy to treat ischemic cerebral injury. Here we investigated 1) whether the protection conferred by sevoflurane preconditioning sustains in time; 2) whether sevoflurane preconditioning diminishes mitochondrial dysfunction following cerebral ischemia; and 3) whether mitochondrial permeability transition pore plays a crucial role in the sevoflurane preconditioning.
Laboratory investigation.
University research laboratory.
: Sprague-Dawley rats.
Rats underwent 2 hrs of focal cerebral ischemia induced by middle cerebral artery occlusion. Preconditioning was elicited with sevoflurane (2.3%) for 60 mins at 24 hrs before ischemia. The involvement of mitochondrial permeability transition pore was determined with a mitochondrial permeability transition pore opener atractyloside and a specific mitochondrial permeability transition pore inhibitor cyclosporin A. In vitro study was performed on acutely isolated mitochondria subjected to calcium overload.
Sevoflurane preconditioning significantly decreased the infarct size by 35.9% (95% confidence interval 6.5-28.4, p < .001). This reduction of injury volume was associated with a long-term improvement of neurological function according to modified neurological severity score (F = 13.6, p = .001) and sticky-tape test (F = 29.1, p < .001) for 42 days after ischemia. Furthermore, sevoflurane preconditioning markedly protected mitochondria, as indicated by preserved respiratory chain complex activities and membrane potential, lowered mitochondrial hydrogen-peroxide production, and attenuated mitochondrial permeability transition pore opening. Isolated mitochondria also demonstrated a reduced sensitivity to Ca-induced mitochondrial permeability transition pore opening after pre-exposure to sevoflurane in vitro (95% confidence interval 24.2-196.5,p = .006). Inhibiting mitochondrial permeability transition pore using cyclosporin A resulted in protective effects similar to those seen with sevoflurane preconditioning, whereas pharmacologically opening the mitochondrial permeability transition pore with atractyloside abrogated all the positive effects of sevoflurane preconditioning and cyclosporin A, including suppression of mitochondrial permeability transition pore opening, counteraction of mitochondria-dependent apoptotic pathway, and subsequent histological and behavioral improvements.
Sevoflurane preconditioning protects mitochondria from cerebral ischemia/reperfusion injury and ameliorates long-term neurological deficits. Inhibition of mitochondrial permeability transition pore opening is a crucial step in mediating the neuroprotection of sevoflurane preconditioning.
麻醉预处理似乎是治疗缺血性脑损伤的一种可行策略。在这里，我们研究了 1）七氟醚预处理所提供的保护是否能持续时间；2）七氟醚预处理是否会减轻脑缺血后的线粒体功能障碍；3）线粒体通透性转换孔是否在七氟醚预处理中发挥关键作用。
实验室研究。
大学研究实验室。
斯普拉格-道利大鼠。
大鼠接受由大脑中动脉闭塞引起的 2 小时局灶性脑缺血。在缺血前 24 小时用七氟醚（2.3%）预处理 60 分钟。用线粒体通透性转换孔开放剂千里光苦毒素和特定的线粒体通透性转换孔抑制剂环孢菌素 A 确定线粒体通透性转换孔的参与情况。在急性分离的线粒体上进行钙超载的体外研究。
七氟醚预处理可显著降低 35.9%的梗死面积（95%置信区间为 6.5-28.4，p<.001）。这种损伤体积的减少与改良神经严重程度评分（F=13.6，p=.001）和胶带测试（F=29.1，p<.001）在缺血后 42 天内长期改善神经功能有关。此外，七氟醚预处理还明显保护线粒体，表现为呼吸链复合物活性和膜电位保持、线粒体过氧化氢产生降低以及线粒体通透性转换孔开放减少。体外预先暴露于七氟醚后，分离的线粒体对 Ca 诱导的线粒体通透性转换孔开放也表现出降低的敏感性（95%置信区间为 24.2-196.5，p=.006）。使用环孢菌素 A 抑制线粒体通透性转换孔可产生与七氟醚预处理相似的保护作用，而用千里光苦毒素药理学开放线粒体通透性转换孔则消除了七氟醚预处理和环孢菌素 A 的所有积极作用，包括抑制线粒体通透性转换孔开放、拮抗线粒体依赖性凋亡途径以及随后的组织学和行为改善。
七氟醚预处理可保护线粒体免受脑缺血/再灌注损伤，并改善长期神经功能缺损。抑制线粒体通透性转换孔开放是介导七氟醚预处理神经保护作用的关键步骤。
