PMID- 25026397 OWN - NLM STAT- MEDLINE DCOM- 20150512 LR - 20220408 IS - 1873-2747 (Electronic) IS - 0361-9230 (Linking) VI - 107 DP - 2014 Aug TI - Both JNK and P38 MAPK pathways participate in the protection by dexmedetomidine against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats. PG - 69-78 LID - S0361-9230(14)00102-6 [pii] LID - 10.1016/j.brainresbull.2014.07.001 [doi] AB - Dexmedetomidine, a highly selective alpha2-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 6h. 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 mug/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 6h. Isoflurane induced significant neuroapoptosis, increased the protein expression of phospho-JNK, phospho-c-Jun, phospho-p38 and phospho-nuclear factor-kappaB (NF-kappaB), 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. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Liao, Zhaoxia AU - Liao Z AD - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: clarice.liao@163.com. FAU - Cao, Dexiong AU - Cao D AD - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: cdx8604@aliyun.com. FAU - Han, Xue AU - Han X AD - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: hanmingxuan@rocketmail.com. FAU - Liu, Chuiliang AU - Liu C AD - Department of Anesthesiology, ChanCheng Center Hospital, Foshan 528030, China. Electronic address: liuchuiliang@hotmail.com. FAU - Peng, Jun AU - Peng J AD - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: pjg_79_1@hotmail.com. FAU - Zuo, Zhiyi AU - Zuo Z AD - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Anesthesiology, University of Virginia Health System, PO Box 800710, Charlottesville, VA 22908-0710, USA. Electronic address: zz3c@hscmail.mcc.virginia.edu. FAU - Wang, Fei AU - Wang F AD - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: 1995wangfei@sina.com.cn. FAU - Li, Yujuan AU - Li Y AD - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: yujuan_04@hotmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140712 PL - United States TA - Brain Res Bull JT - Brain research bulletin JID - 7605818 RN - 0 (Adrenergic alpha-2 Receptor Agonists) RN - 0 (Neuroprotective Agents) RN - 67VB76HONO (Dexmedetomidine) RN - CYS9AKD70P (Isoflurane) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 2.7.12.2 (MAP Kinase Kinase 4) SB - IM MH - Adrenergic alpha-2 Receptor Agonists/pharmacology MH - Animals MH - Animals, Newborn MH - Apoptosis/*drug effects MH - Dexmedetomidine/*pharmacology MH - Hippocampus/drug effects/*metabolism MH - Isoflurane/*toxicity MH - MAP Kinase Kinase 4/*metabolism MH - Neurons/drug effects/metabolism MH - Neuroprotective Agents/*pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction MH - p38 Mitogen-Activated Protein Kinases/*metabolism OTO - NOTNLM OT - Apoptosis OT - Caspase-3 OT - Dexmedetomidine OT - Isoflurane OT - Mitogen-activated protein kinase (MAPK) EDAT- 2014/07/16 06:00 MHDA- 2015/05/13 06:00 CRDT- 2014/07/16 06:00 PHST- 2014/05/16 00:00 [received] PHST- 2014/07/01 00:00 [revised] PHST- 2014/07/03 00:00 [accepted] PHST- 2014/07/16 06:00 [entrez] PHST- 2014/07/16 06:00 [pubmed] PHST- 2015/05/13 06:00 [medline] AID - S0361-9230(14)00102-6 [pii] AID - 10.1016/j.brainresbull.2014.07.001 [doi] PST - ppublish SO - Brain Res Bull. 2014 Aug;107:69-78. doi: 10.1016/j.brainresbull.2014.07.001. Epub 2014 Jul 12.