Both JNK and P38 MAPK pathways participate in the protection by dexmedetomidine against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats
Both JNK and P38 MAPK pathways participate in the protection by dexmedetomidine against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats
复制标题
JNK和P38 MAPK通路均参与右美托咪定对异氟烷诱导的新生大鼠海马神经细胞凋亡的保护作用
DOI：
10.1016/j.brainresbull.2014.07.001
复制
发表时间：
2014-08-01
影响因子：
3.8
通讯作者：
Li, Yujuan
中科院分区：
文献类型：
--
作者：
Liao, Zhaoxia;Cao, Dexiong;Li, Yujuan
右美托咪定是一种高选择性α 2-肾上腺素能激动剂，据报道可减轻异氟烷诱导的认知障碍和神经细胞凋亡。然而，潜在的分子机制仍然知之甚少。本研究的目的是研究丝裂原活化蛋白激酶（MAPK）通路是否参与右美托咪定诱导的神经保护作用。用不同浓度的右美托咪定预处理7日龄（P7）新生Sprague-Dawley大鼠，然后暴露于0.75%异氟烷或空气中6 h。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）检测海马神经元凋亡。Western blotting检测海马区活化的caspase-3、细胞外信号调节激酶1/2（ERK 1/2）、c-Jun氨基末端激酶（JNK）、p38、磷酸化ERK 1/2、磷酸化JNK和磷酸化p38蛋白。此外，P7大鼠单独用75 μ g/kg右旋美托咪啶预处理，或在右旋美托咪啶预处理之前给予ERK抑制剂U 0126，或单独用p38 MAPK抑制剂SB 203580或JNK抑制剂SP 600125预处理，然后暴露于0.75%异氟烷6小时。异氟醚诱导海马神经细胞凋亡，增加磷酸化JNK、磷酸化c-Jun、磷酸化p38和磷酸化核因子-κ B（NF-κ B）蛋白表达，降低磷酸化ERK 1/2蛋白水平，降低Bcl-2/Bax比值。右美托咪定预处理可抑制异氟烷诱导的神经细胞凋亡，并恢复MAPK通路的蛋白表达和异氟烷暴露后的Bcl-2/Bax比值。此外，SB 203580和SP 600125也部分减弱了异氟醚诱导的蛋白质变化。然而，U 0126没有逆转右美托咪定诱导的神经保护作用。我们的研究结果表明，JNK和p38通路，而不是ERK通路参与右美托咪定诱导的神经保护对异氟烷的影响。(C)2014 Elsevier Inc. All rights reserved.
Dexmedetomidine, a highly selective alpha 2-adrenergic agonist, has been reported to attenuate isoflurane-induced cognitive impairment and neuroapoptosis. However, the underlying molecular mechanisms remain poorly understood. The aim of this study was to investigate whether mitogen-activated protein kinase (MAPK) pathway was involved in dexmedetomidine-induced neuroprotection against isoflurane effects. Seven-day-old (P7) neonatal Sprague-Dawley rats were pretreated with various concentrations of dexmedetomidine, and then exposed to 0.75% isoflurane or air for 6 h. Terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL) was used to detect neuronal apoptosis in their hippocampus. Activated caspase-3, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinases (JNK), p38, phospho-ERK1/2, phospho-JNK and phospho-p38 proteins were detected by Western blotting in the hippocampus at the end of exposure. Also, P7 rats were pretreated with 75 mu g/kg dexmedetomidine alone, or given the ERK inhibitor U0126 before dexmedetomidine pretreatment, or pretreated with the p38 MAPK inhibitor SB203580 or JNK inhibitor SP600125 alone, and then exposed to 0.75% isoflurane for 6 h. Isoflurane induced significant neuroapoptosis, increased the protein expression of phospho-JNK, phospho-c-Jun, phospho-p38 and phospho-nuclear factor-kappa B (NF-kappa B), decreased the level of phospho-ERK1/2 protein and reduced the ratio of Bcl-2/Bax in the hippocampus. Dexmedetomidine pretreatment inhibited isoflurane-induced neuroapoptosis and restored proteins expression of MAPK pathways and the Bcl-2/Bax ratio after isoflurane exposure. Moreover, SB203580 and SP600125 also partly attenuated the isoflurane-induced protein changes. However, U0126 did not reverse dexmedetomidine-induced neuroprotection. Our results indicate that the JNK and p38 pathways, not the ERK pathway are involved in dexmedetomidine-induced neuroprotection against isoflurane effects. (C) 2014 Elsevier Inc. All rights reserved.