Pharmacological inhibition of PTEN attenuates cognitive deficits caused by neonatal repeated exposures to isoflurane via inhibition of NR2B-mediated tau phosphorylation in rats
Pharmacological inhibition of PTEN attenuates cognitive deficits caused by neonatal repeated exposures to isoflurane via inhibition of NR2B-mediated tau phosphorylation in rats
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DOI：
10.1016/j.neuropharm.2016.11.008
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发表时间：
2017-03
影响因子：
4.7
通讯作者：
L. Tan;Xin Chen;Wei Wang;Jianfang Zhang;Shiyong Li;Yilin Zhao;Jin-tao Wang;A. Luo
中科院分区：
文献类型：
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作者：
L. Tan;Xin Chen;Wei Wang;Jianfang Zhang;Shiyong Li;Yilin Zhao;Jin-tao Wang;A. Luo
有证据表明，在儿童早期暴露于反复麻醉的儿童表现出长期的认知障碍。然而，基本机制在很大程度上仍不清楚。我们以前的研究表明，参与磷酸酶和张力蛋白同源物10号染色体上删除（PTEN）在异氟烷诱导的海马神经前体细胞自我更新能力的下降。此外，其他人证明，在阿尔茨海默病模型中，PTEN抑制可以通过减少tau磷酸化来保护认知障碍。因此，在目前的体内研究中，我们的目的是检查PTEN抑制对新生儿反复暴露于异氟烷引起的认知功能障碍和tau蛋白过度磷酸化的影响。我们的结果表明，新生儿重复暴露于异氟烷会导致海马中PTEN的激活。PTEN抑制剂BPV（pic）的治疗恢复了PSD-95的合成，并减弱了tau磷酸化以及由反复异氟烷暴露引起的认知功能障碍。此外，BPV（pic）处理逆转了反复暴露于异氟烷诱导的含NR 2B的NMDAR的激活，而反过来，艾芬地尔对NR 2B亚基的拮抗作用减轻了tau磷酸化，表明NR 2B作为PTEN的下游在反复暴露于异氟烷的新生大鼠中介导tau磷酸化中可能起作用。总之，我们的研究结果揭示了PTEN在介导tau蛋白磷酸化和新生儿反复暴露于异氟烷引起的认知缺陷中的新作用，这意味着靶向PTEN可能是发育中大脑中麻醉相关认知下降的潜在治疗方法。
Evidence has shown that children exposed to repeated anesthesia in early childhood display long-term cognitive disabilities. However, the underlying mechanisms remain largely unclear. Our previous study has indicated the involvement of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in isoflurane-induced decrease of self-renewal capacity in hippocampal neural precursor cells. Additionally, it is demonstrated by others that PTEN inhibition could protect against cognitive impairment via reduction of tau phosphorylation in the alzheimer's disease model. Therefore, in the presentin vivostudy, we aimed to examine the effects of PTEN inhibition on the cognitive dysfunction and tau hyperphosphorylation caused by neonatal repeated exposures to isoflurane. Our results showed that the neonatal repeated exposures to isoflurane resulted in the activation of PTEN in the hippocampus. The treatment of PTEN inhibitor BPV (pic) restored PSD-95 synthesis, and attenuated tau phosphorylation as well as the cognitive dysfunction caused by the repeated isoflurane exposures. In addition, BPV (pic) treatment reversed the activation of NR2B-containing NMDARs induced by repeated isoflurane exposures, while in turn, the antagonism of NR2B subunit with ifenprodil alleviated tau phosphorylation, indicating a possible role of NR2B as the downstream of PTEN in mediating tau phosphorylation in the neonatal rats repeatedly exposed to isoflurane. In conclusion, our results reveal a novel role of PTEN in mediating tau phosphorylation and cognitive deficits caused by neonatal repeated exposures to isoflurane, implying that targeting on PTEN may be a potential therapeutic approach for the anesthetic-related cognitive decline in the developing brain.