Wang Ning, Lu Yang, Wang Kui, Li Wei-Song, Lu Pan, Lei Shan, Li Rong, Zhang Hong, Zheng Juan, Lu Hai-Xia, Chen Xin-Lin, Liu Yong, Zhang Peng-Bo
Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China.
Institute of Neurobiology, National Key Academic Subject of Physiology of Xi'an Jiaotong University, Shaanxi, China.
Cell Physiol Biochem. 2018;46(2):618-632. doi: 10.1159/000488630. Epub 2018 Mar 28.
BACKGROUND/AIMS: Isoflurane inhibited neurogenesis and induced subsequent neurocognitive deficits in developing brain. Simvastatin exerts neuroprotection in a wide range of brain injury models. In the present study, we investigated whether simvastatin could attenuate neurogenetic inhibition and cognitive deficits induced by isoflurane exposure in neonatal rats.
Sprague-Dawley rats at postnatal day (PND) 7 and neural stem cells (NSCs) were treated with either gas mixture, isoflurane, or simvastatin 60 min prior to isoflurane exposure, respectively. The rats were decapitated at PND 8 and PND 10 for detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. NSC proliferation, viability and apoptosis were assessed by immunohistochemistry, CCK-8 and TUNEL, respectively. The protein expressions of caspase-3, p-Akt and p-GSK-3β both in vivo and vitro were assessed by western blotting. Cognitive functions were assessed by Morris Water Maze test and context fear conditioning test at the adult.
Isoflurane exposure inhibited neurogenesis in the SVZ and SGZ, decreased NSC proliferation and viability, promoted NSC apoptosis and led to late cognitive deficits. Furthermore, isoflurane increased caspase-3 expression and decreased protein expressions of p-Akt and p-GSK-3β both in vivo and in vitro. Pretreatment with simvastatin attenuated isoflurane-elicited changes in NSCs and cognitive function. Co-treatment with LY294002 reversed the effect of simvastatin on NSCs in vitro.
We for the first time showed that simvastatin, by upregulating Akt/GSK-3β signaling pathway, alleviated isoflurane-induced neurogenetic damage and neurocognitive deficits in developing rat brain.
背景/目的：异氟烷抑制发育中大脑的神经发生并导致随后的神经认知缺陷。辛伐他汀在多种脑损伤模型中发挥神经保护作用。在本研究中，我们调查了辛伐他汀是否能减轻异氟烷暴露诱导的新生大鼠神经发生抑制和认知缺陷。
分别在出生后第7天（PND7）的Sprague-Dawley大鼠和神经干细胞（NSCs）在异氟烷暴露前60分钟用混合气体、异氟烷或辛伐他汀处理。在PND8和PND10将大鼠断头，通过免疫染色检测海马体室下区（SVZ）和颗粒下区（SGZ）的神经发生。分别通过免疫组化、CCK-8和TUNEL评估神经干细胞的增殖、活力和凋亡。通过蛋白质印迹法评估体内和体外caspase-3、p-Akt和p-GSK-3β的蛋白表达。在成年期通过莫里斯水迷宫试验和情境恐惧条件试验评估认知功能。
异氟烷暴露抑制了SVZ和SGZ中的神经发生，降低了神经干细胞的增殖和活力，促进了神经干细胞凋亡并导致后期认知缺陷。此外，异氟烷在体内和体外均增加了caspase-3表达，并降低了p-Akt和p-GSK-3β的蛋白表达。辛伐他汀预处理减轻了异氟烷引起的神经干细胞和认知功能变化。与LY294002共同处理可逆转辛伐他汀在体外对神经干细胞的作用。
我们首次表明，辛伐他汀通过上调Akt/GSK-3β信号通路，减轻了异氟烷诱导的发育中大鼠脑的神经发生损伤和神经认知缺陷。
