Activation of Autophagy Contributes to Sevoflurane-Induced Neurotoxicity in Fetal Rats.
Activation of Autophagy Contributes to Sevoflurane-Induced Neurotoxicity in Fetal Rats.
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DOI：
10.3389/fnmol.2017.00432
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发表时间：
2017
影响因子：
4.8
通讯作者：
Zhao P
中科院分区：
文献类型：
--
作者：
Li X;Wu Z;Zhang Y;Xu Y;Han G;Zhao P
许多动物研究表明，常用的全身麻醉剂可能会导致未成熟大脑的认知障碍。目前流行的理论认为，全身麻醉药可通过促进细胞凋亡诱导发育神经毒性。此外，还报道了由麻醉剂诱导的抑制增殖。到目前为止，是否自噬，一个保守的细胞过程，是细胞命运的关键，也参与麻醉诱导的神经毒性仍然是难以捉摸的。在这里，我们首先研究了七氟烷暴露后自噬相关的变化以及自噬对细胞凋亡和增殖的影响，我们还探讨了自噬激活的潜在机制。妊娠大鼠在妊娠第14天（G14）暴露于2%或3.5%七氟烷2 h;然后，在麻醉后2、12、24和48 h测量胎仔脑中自噬标志物和自噬途径组分的表达。在给予自噬或PTEN抑制剂后，检查神经干细胞（NSC）凋亡、神经发生、神经元数量和学习记忆功能的变化。在3.5%七氟烷组中，微管相关蛋白1轻链3（LC 3）-II、Beclin-1和10号染色体上的磷酸酶和张力蛋白同源物（PTEN）的表达增加，而Sequestosome 1（P62/SQSTM 1）、磷酸化蛋白激酶B/蛋白激酶B（p-Akt/Akt）和哺乳动物雷帕霉素靶蛋白（mTOR）的表达降低。3-甲基腺嘌呤（3-MA），自噬抑制剂，或二钾双过氧-PTEN抑制剂（5-羟基吡啶-2-羧基）-氧钒酸盐（V）（bpV）可显著减弱自噬的激活，逆转B细胞淋巴瘤-2（Bcl-2）表达的下降，减少末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）阳性细胞数，改善Nestin表达的下降，Ki 67阳性细胞率、神经元数量和越平台次数，并缩短延长的逃避潜伏期。我们的研究结果表明，在G14时暴露于3.5%七氟烷2 h可通过PTEN/Akt/mTOR通路诱导胎脑过度自噬。自噬抑制逆转麻醉诱导的NSC凋亡、增殖下降和记忆缺陷。
Numerous animal studies have demonstrated that commonly used general anesthetics may result in cognitive impairment in the immature brain. The prevailing theory is that general anesthetics could induce developmental neurotoxicity via enhanced apoptosis. In addition, inhibited proliferation induced by anesthetics has also been reported. So far, whether autophagy, a well-conserved cellular process that is critical for cell fate, also participates in anesthesia-induced neurotoxicity remains elusive. Here, we first examined autophagy-related changes after sevoflurane exposure and the effect of autophagy on apoptosis and proliferation, and we also explored the underlying mechanisms of autophagy activation. Pregnant rats were exposed to 2 or 3.5% sevoflurane for 2 h on gestational day 14 (G14); then, markers of autophagy and expression of autophagy pathway components were measured in fetal brains 2, 12, 24, and 48 h after anesthesia. Changes in neural stem cell (NSC) apoptosis, neurogenesis, neuron quantity and learning and memory function were examined after administration of an autophagy or PTEN inhibitor. The expression of microtubule-associated protein 1 light chain 3 (LC3)-II, Beclin-1 and phosphatase and tensin homolog on chromosome 10 (PTEN) were increased in the 3.5% sevoflurane group, while Sequestosome 1 (P62/SQSTM1), phospho-protein kinase B/protein kinase B (p-Akt/Akt) and mammalian target of rapamycin (mTOR) were decreased. 3-methyladenine (3-MA), an inhibitor of autophagy, or dipotassium bisperoxo-(5-hydroxypyridine-2-carboxyl)-oxovanadate (V) (bpV), a PTEN inhibitor, significantly attenuated the activation of autophagy, reversed the decreased expression of B-cell lymphoma-2 (Bcl-2) and reduced the number of terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) positive cells, ameliorated the decline of Nestin expression, Ki67 positive cell rate, neuron quantity and cross platform times, and shortened the prolonged escape latency. Our results demonstrated that 2 h 3.5% sevoflurane exposure at G14 induced excessive autophagy in the fetal brain via the PTEN/Akt/mTOR pathway. Autophagy inhibition reversed anesthesia-induced NSC apoptosis, proliferation decline and memory deficits.
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影响因子：
64.8
作者：
Fimia, Gian Maria;Stoykova, Anastassia;Cecconi, Francesco
通讯作者：
Cecconi, Francesco
影响因子：
5.3
作者：
De Amicis F;Guido C;Santoro M;Lanzino M;Panza S;Avena P;Panno ML;Perrotta I;Aquila S;Andò S
通讯作者：
Andò S
影响因子：
13.3
作者：
Chen, Gang;Ke, Zunji;Luo, Jia
通讯作者：
Luo, Jia
影响因子：
3.8
作者：
Orrenius, Sten;Nicotera, Pierluigi;Zhivotovsky, Boris
通讯作者：
Zhivotovsky, Boris
早期发育接触挥发性麻醉剂会导致秀丽隐杆线虫的行为缺陷。
影响因子：
5.7
作者：
Gentry KR;Steele LM;Sedensky MM;Morgan PG
通讯作者：
Morgan PG