Sevoflurane preconditioning-induced neuroprotection is associated with Akt activation via carboxy-terminal modulator protein inhibition
Sevoflurane preconditioning-induced neuroprotection is associated with Akt activation via carboxy-terminal modulator protein inhibition
复制标题
七氟烷预处理诱导的神经保护作用通过羧基末端调节蛋白抑制与 Akt 激活相关。
DOI：
10.1093/bja/aeu271
复制
发表时间：
2015-02-01
影响因子：
9.8
通讯作者：
Xiong, L.
中科院分区：
文献类型：
--
作者：
Chen, Y.;Nie, H.;Xiong, L.
背景七氟醚预处理具有神经保护作用，但其机制尚不完全清楚。本研究的目的是评估七氟烷诱导的脑预处理是否涉及抑制羧基末端调节蛋白（CTMP），一种内源性Akt抑制剂，在大鼠局灶性脑缺血模型。将雄性Sprague-Dawley大鼠暴露于2.7%七氟烷45分钟。1小时后，对大鼠进行60分钟的局灶性脑缺血。在预处理前10 min给予磷酸肌醇3-激酶抑制剂wortmannin和LY 294002。慢病毒转导组大鼠在缺血前3天接受脑室内注射慢病毒载体Ubi-MCS-CTMP。再灌注后24小时和7天评估神经功能缺损和梗死体积。在再灌注后1、3、12和24 h测定Akt磷酸化、糖原合成酶激酶-3 β（GSK 3 β）和CTMP表达。再灌注3 h后测定Akt活性。七氟醚预处理改善了神经功能评分，并减少了再灌注24小时的梗死面积。预处理wortmannin或LY 294002减弱这些神经保护作用。CTMP的表达与缺血后Akt活性降低相关，而七氟烷预处理保留了Akt活性并增加了GSK 3 β的磷酸化。CTMP过度表达减弱了七氟烷预处理的有益作用。通过抑制CTMP激活Akt信号参与七氟烷预处理提供的神经保护机制。
Background. Sevoflurane preconditioning has a neuroprotective effect, but the underlying mechanism is not fully understood. The aim of the present investigation was to evaluate whether sevoflurane-induced cerebral preconditioning involves inhibition of carboxy-terminal modulator protein (CTMP), an endogenous inhibitor of Akt, in a rat model of focal cerebral ischaemia.Methods. Male Sprague-Dawley rats were exposed to 2.7% sevoflurane for 45 min. One hour later, rats were subjected to 60 min of focal cerebral ischaemia. The phosphoinositide 3-kinase inhibitors wortmannin and LY294002 were administered 10 min before preconditioning. Rats in the lentiviral transduction group received an intracerebroventricular injection of lentiviral vector Ubi-MCS-CTMP 3 days before ischaemia. Neurological deficits and infarct volumes were evaluated 24 h and 7 days after reperfusion. Phosphorylation of Akt, glycogen synthase kinase-3 beta (GSK3 beta), and expression of CTMP were determined at 1, 3, 12, and 24 h after reperfusion. Akt activity was measured at 3 h after reperfusion.Results. Sevoflurane preconditioning improved neurological score and reduced infarct size at 24 h of reperfusion. Pretreatment with wortmannin or LY294002 attenuated these neuroprotective effects. Expression of CTMP correlated with reduced Akt activity after ischaemia, while sevoflurane preconditioning preserved Akt activity and increased phosphorylation of GSK3 beta. CTMP over-expression diminished the beneficial effects of sevoflurane preconditioning.Conclusions. Activation of Akt signalling via inhibition of CTMP is involved in the mechanism of neuroprotection provided by sevoflurane preconditioning.