Dexmedetomidine reduces isoflurane-induced neuroapoptosis partly by preserving PI3K/Akt pathway in the hippocampus of neonatal rats.
Dexmedetomidine reduces isoflurane-induced neuroapoptosis partly by preserving PI3K/Akt pathway in the hippocampus of neonatal rats.
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DOI：
10.1371/journal.pone.0093639
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Peng S
中科院分区：
文献类型：
--
作者：
Li Y;Zeng M;Chen W;Liu C;Wang F;Han X;Zuo Z;Peng S
长时间暴露于挥发性麻醉剂，如异氟烷和七氟烷，会导致发育中的动物大脑神经退行性变。最近的研究表明，右美托咪定，一种选择性α2-肾上腺素能激动剂，减少异氟醚诱导的认知障碍和神经细胞凋亡。然而，其作用机制尚不完全清楚。因此，我们研究了在大脑发育期间以等效剂量暴露于异氟烷或七氟烷用于麻醉是否会导致不同程度的神经细胞凋亡，以及右美托咪定是否通过对可调节细胞存活的PI 3 K/Akt通路的影响来减少这种神经细胞凋亡。将7日龄（P7）新生Sprague-Dawley大鼠随机暴露于0.75%异氟烷、1.2%七氟烷或空气中6 h。免疫组化和Western blotting检测caspase-3活性。Western blotting检测海马组织中磷酸化Akt、磷酸化Bad、Akt、Bad和Bcl-xL蛋白的表达。此外，P7大鼠用各种浓度的右旋美托咪啶单独或与PI 3 K抑制剂LY 294002一起预处理，然后暴露于0.75%异氟烷。采用末端脱氧核糖核苷酸转移酶介导的dUTP缺口末端标记法（TUNEL）和活化的caspase-3检测海马神经元凋亡。异氟烷而非等效剂量的七氟烷诱导了显著的神经细胞凋亡，降低了海马中磷酸化Akt和磷酸化Bad蛋白的水平，增加了Bad蛋白的表达，并降低了Bcl-xL/Bad的比值。右美托咪定预处理剂量依赖性地抑制异氟烷诱导的神经细胞凋亡，恢复磷酸化Akt和Bad的蛋白表达以及异氟烷诱导的Bcl-xL/Bad比值。75 µg/kg右美托咪定单次给药预处理提供的保护作用与25 µg/kg右美托咪定三次给药相似。此外，LY 294002部分抑制右旋美托咪啶的神经保护作用。我们的研究结果表明，右美托咪定预处理提供了神经保护，对异氟烷诱导的新生大鼠海马神经细胞凋亡，通过保护PI 3 K/Akt通路的活性。
Prolonged exposure to volatile anesthetics, such as isoflurane and sevoflurane, causes neurodegeneration in the developing animal brains. Recent studies showed that dexmedetomidine, a selective α2-adrenergic agonist, reduced isoflurane-induced cognitive impairment and neuroapoptosis. However, the mechanisms for the effect are not completely clear. Thus, we investigated whether exposure to isoflurane or sevoflurane at an equivalent dose for anesthesia during brain development causes different degrees of neuroapoptosis and whether this neuroapoptosis is reduced by dexmedetomidine via effects on PI3K/Akt pathway that can regulate cell survival. Seven-day-old (P7) neonatal Sprague-Dawley rats were randomly exposed to 0.75% isoflurane, 1.2% sevoflurane or air for 6 h. Activated caspase-3 was detected by immunohistochemistry and Western blotting. Phospho-Akt, phospho-Bad, Akt, Bad and Bcl-xL proteins were detected by Western blotting in the hippocampus at the end of exposure. Also, P7 rats were pretreated with various concentrations of dexmedetomidine alone or together with PI3K inhibitor LY294002, and then exposed to 0.75% isoflurane. Terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL) and activated caspase-3 were used to detect neuronal apoptosis in their hippocampus. Isoflurane, not sevoflurane at the equivalent dose, induced significant neuroapoptosis, decreased the levels of phospho-Akt and phospho-Bad proteins, increased the expression of Bad protein and reduced the ratio of Bcl-xL/Bad in the hippocampus. Dexmedetomidine pretreatment dose-dependently inhibited isoflurane-induced neuroapoptosis and restored protein expression of phospho-Akt and Bad as well as the Bcl-xL/Bad ratio induced by isoflurane. Pretreatment with single dose of 75 µg/kg dexmedetomidine provided a protective effect similar to that with three doses of 25 µg/kg dexmedetomidine. Moreover, LY294002, partly inhibited neuroprotection of dexmedetomidine. Our results suggest that dexmedetomidine pretreatment provides neuroprotection against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats by preserving PI3K/Akt pathway activity.
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