Yin Jinbo, Li Hong, Feng Chenzhuo, Zuo Zhiyi
Department of Anesthesiology, University of Virginia Health System, 1 Hospital Drive, PO Box 800710, Charlottesville, Virginia 22908-0710, USA.
CNS Neurol Disord Drug Targets. 2014;13(4):718-32. doi: 10.2174/1871527313666140618110837.
Prolonged exposure to volatile anesthetics alone may be detrimental to the brain. However, volatile anesthetics, such as isoflurane, can provide neuroprotection against various damaging insults. Application of isoflurane after focal brain ischemia reduces ischemic brain injury. We determined whether this isoflurane postconditioning-induced neuroprotection requires inhibition of brain ischemia-induced Notch signaling activation. Here, we showed that TUNEL-positive staining cell density and active caspase 3 expression were increased in the ischemic penumbral brain tissues of male rats after a 90-min middle cerebral arterial occlusion (MCAO). This increase was inhibited by isoflurane postconditioning and a Notch inhibitor. Isoflurane postconditioning and the Notch inhibitor also inhibited brain ischemia-induced Notch activation and proinflammatory cytokine production. Most cells expressing active Notch also were positive for CD11b, a microglial and white blood cell marker. Isoflurane postconditioning and the Notch inhibitor inhibited 1 ng/ml lipopolysaccharide- and oxygen-glucose deprivation-induced Notch activation and proinflammatory cytokine production from microglial cultures. The inhibition of cytokine production by isoflurane postconditioning, but not by a high concentration of the Notch inhibitor, disappeared in the presence of 10 ng/ml lipopolysaccharide. Our results suggest that Notch activation in microglia contributes to the cell apoptosis in the ischemic brain tissues. Inhibiting this Notch activation may participate in isoflurane postconditioning-induced neuroprotection against transient focal brain ischemia in male rats.
单独长时间暴露于挥发性麻醉剂可能对大脑有害。然而，挥发性麻醉剂，如异氟烷，可针对各种损伤性刺激提供神经保护作用。局灶性脑缺血后应用异氟烷可减轻缺血性脑损伤。我们确定异氟烷后处理诱导的神经保护作用是否需要抑制脑缺血诱导的Notch信号激活。在此，我们发现，在雄性大鼠大脑中动脉闭塞（MCAO）90分钟后，缺血半暗带脑组织中TUNEL阳性染色细胞密度和活化的半胱天冬酶3表达增加。异氟烷后处理和Notch抑制剂可抑制这种增加。异氟烷后处理和Notch抑制剂还可抑制脑缺血诱导的Notch激活和促炎细胞因子产生。大多数表达活化Notch的细胞也呈小胶质细胞和白细胞标志物CD11b阳性。异氟烷后处理和Notch抑制剂可抑制小胶质细胞培养物中1 ng/ml脂多糖和氧-葡萄糖剥夺诱导的Notch激活和促炎细胞因子产生。在存在10 ng/ml脂多糖的情况下，异氟烷后处理对细胞因子产生的抑制作用消失，但高浓度的Notch抑制剂则无此作用。我们的结果表明，小胶质细胞中的Notch激活促成了缺血脑组织中的细胞凋亡。抑制这种Notch激活可能参与异氟烷后处理诱导的对雄性大鼠短暂局灶性脑缺血的神经保护作用。
