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Activation of Autophagy Contributes to Sevoflurane-Induced Neurotoxicity in Fetal Rats.
Front Mol Neurosci. 2017; 10:432.FM

Abstract

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.

Authors+Show Affiliations

Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29311820

Citation

Li, Xingyue, et al. "Activation of Autophagy Contributes to Sevoflurane-Induced Neurotoxicity in Fetal Rats." Frontiers in Molecular Neuroscience, vol. 10, 2017, p. 432.
Li X, Wu Z, Zhang Y, et al. Activation of Autophagy Contributes to Sevoflurane-Induced Neurotoxicity in Fetal Rats. Front Mol Neurosci. 2017;10:432.
Li, X., Wu, Z., Zhang, Y., Xu, Y., Han, G., & Zhao, P. (2017). Activation of Autophagy Contributes to Sevoflurane-Induced Neurotoxicity in Fetal Rats. Frontiers in Molecular Neuroscience, 10, 432. https://doi.org/10.3389/fnmol.2017.00432
Li X, et al. Activation of Autophagy Contributes to Sevoflurane-Induced Neurotoxicity in Fetal Rats. Front Mol Neurosci. 2017;10:432. PubMed PMID: 29311820.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of Autophagy Contributes to Sevoflurane-Induced Neurotoxicity in Fetal Rats. AU - Li,Xingyue, AU - Wu,Ziyi, AU - Zhang,Yi, AU - Xu,Ying, AU - Han,Guang, AU - Zhao,Ping, Y1 - 2017/12/22/ PY - 2017/09/25/received PY - 2017/12/15/accepted PY - 2018/1/10/entrez PY - 2018/1/10/pubmed PY - 2018/1/10/medline KW - apoptosis KW - autophagy KW - cognitive impairment KW - midtrimester KW - neural stem cells KW - neurogenesis KW - neurotoxicity KW - sevoflurane SP - 432 EP - 432 JF - Frontiers in molecular neuroscience JO - Front Mol Neurosci VL - 10 N2 - 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. SN - 1662-5099 UR - https://www.unboundmedicine.com/medline/citation/29311820/Activation_of_Autophagy_Contributes_to_Sevoflurane_Induced_Neurotoxicity_in_Fetal_Rats_ L2 - https://doi.org/10.3389/fnmol.2017.00432 DB - PRIME DP - Unbound Medicine ER -
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