title: Both JNK and P38 MAPK pathways participate in the protection by dexmedetomidine against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats.
abstract: Dexmedetomidine, a highly selective α2-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 μg/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-κB (NF-κB), 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.
authors.affiliation: Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: clarice.liao@163.com.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Liao
authors.affiliation: Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: cdx8604@aliyun.com.
authors.forename: Dexiong
authors.initials: D
authors.lastname: Cao
authors.affiliation: Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: hanmingxuan@rocketmail.com.
authors.forename: Xue
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Anesthesiology, ChanCheng Center Hospital, Foshan 528030, China. Electronic address: liuchuiliang@hotmail.com.
authors.forename: Chuiliang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: pjg_79_1@hotmail.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: 1995wangfei@sina.com.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: yujuan_04@hotmail.com.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Li
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D020927:Dexmedetomidine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007530:Isoflurane / Q000633:toxicity*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D018696:Neuroprotective Agents; D020927:Dexmedetomidine; D007530:Isoflurane; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4
keywords: Apoptosis; Caspase-3; Dexmedetomidine; Isoflurane; Mitogen-activated protein kinase (MAPK)