Chen Xin, Wang Wei, Zhang Jianfang, Li Shiyong, Zhao Yilin, Tan Lei, Luo Ailin
Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Brain Res. 2015 Nov 2;1625:275-86. doi: 10.1016/j.brainres.2015.08.047. Epub 2015 Sep 11.
Evidence has shown that children exposed to isoflurane anesthesia in early childhood display long-term cognitive abnormalities, and decreased self-renewal capacity of hippocampal neural precursor cells (NPCs), which are associated with cognition impairment. Caspase-3 has long been considered as a mediator in isoflurane-induced neuroapoptosis. However, accumulating data indicate that caspase-3 also plays a non-apoptotic negative regulatory role in NPCs self-renewal. In this study we used in vitro NPC cultures to test whether caspase-3 and its downstream signaling effectors were involved in isoflurane-induced impairment of the self-renewal capacity of hippocampal NPCs. We showed that isoflurane exposure induced a decrease in the self-renewal capacity of hippocampal NPCs by decreasing proliferation and increasing neuronal differentiation. Furthermore, we found that isoflurane exposure significantly increased the levels of active caspase-3 and decreased the levels of phospho-PTEN under both proliferation and differentiation conditions. Inhibition of either caspase-3 with Z-DEVD-fmk or PTEN with BPV (phen) in NPCs, attenuated the isoflurane-induced decrease of their proliferation and increase of neuronal differentiation. Application of Z-DEVD-fmk also attenuated isoflurane-induced decrease in phospho-PTEN expression. Taken together, our in vitro results reveal a previously uncharacterized involvement of caspase-3/PTEN signaling in the isoflurane-induced impairment of NPCs self-renewal, and contribute to the identification of novel targets for maintaining NPCs self-renewal in isoflurane-induced cognitive dysfunction.
有证据表明，幼儿期接触异氟烷麻醉的儿童表现出长期认知异常，以及海马神经前体细胞（NPCs）自我更新能力下降，这与认知障碍有关。长期以来，半胱天冬酶-3一直被认为是异氟烷诱导神经细胞凋亡的介质。然而，越来越多的数据表明，半胱天冬酶-3在NPCs自我更新中也发挥着非凋亡性的负调节作用。在本研究中，我们使用体外NPC培养来测试半胱天冬酶-3及其下游信号效应器是否参与异氟烷诱导的海马NPCs自我更新能力损伤。我们发现，异氟烷暴露通过减少增殖和增加神经元分化，导致海马NPCs自我更新能力下降。此外，我们发现，在增殖和分化条件下，异氟烷暴露均显著增加了活性半胱天冬酶-3的水平，并降低了磷酸化PTEN的水平。在NPCs中用Z-DEVD-fmk抑制半胱天冬酶-3或用BPV（苯）抑制PTEN，均可减弱异氟烷诱导的增殖减少和神经元分化增加。应用Z-DEVD-fmk也减弱了异氟烷诱导的磷酸化PTEN表达下降。综上所述，我们的体外研究结果揭示了半胱天冬酶-3/PTEN信号通路在异氟烷诱导的NPCs自我更新损伤中的一种前所未有的作用，并有助于确定在异氟烷诱导的认知功能障碍中维持NPCs自我更新的新靶点。
