Neuroprotective effects of valproic acid against hemin toxicity: Possible involvement of the down-regulation of heme oxygenase-1 by regulating ubiquitin-proteasomal pathway

被引：27

作者：

Kwon, Kyoung Ja ^{[1
]}

Kim, Jung Nam ^{[2
]}

Kim, Min Kyeong ^{[2
]}

Kim, Su Young ^{[2
]}

Cho, Kyu Suk ^{[1
]}

Jeon, Se Jin ^{[2
]}

Kim, Hahn Young ^{[1
]}

Ryu, Jong Hoon ^{[3
,4
]}

Han, Sun-Young ^{[5
]}

Cheong, Jae Hoon ^{[6
]}

Ignarro, Louis J. ^{[7
,8
]}

Han, Seol-Heui ^{[1
]}

Shin, Chan Young ^{[2
]}

机构：

[1] Konkuk Univ, Sch Med, SMART Inst Adv Biomed Sci, Neurosci Res Ctr,Dept Neurol, Seoul 143701, South Korea

[2] Konkuk Univ, Sch Med, SMART Inst Adv Biomed Sci, Neurosci Res Ctr,Dept Pharmacol, Seoul 143701, South Korea

[3] Kyung Hee Univ, Coll Pharm, Dept Oriental Pharmaceut Sci, Seoul 130701, South Korea

[4] Kyung Hee Univ, Coll Pharm, Kyung Hee East West Pharmaceut Res Inst, Seoul 130701, South Korea

[5] Gyeongsang Natl Univ, Life Sci Res Inst, Coll Pharm, Jinju 660751, Gyeongnam, South Korea

[6] Sahmyook Univ, Coll Pharm, Seoul 139742, South Korea

[7] Konkuk Univ, Seoul 143701, South Korea

[8] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

来源：

NEUROCHEMISTRY INTERNATIONAL | 2013年 / 62卷 / 03期

基金：

新加坡国家研究基金会;

关键词：

Valproic acid; Heme oxygenase-1; Ubiquitin-proteasome pathway; Neuroprotection; Intracerebral hemorrhage; Stroke; HISTONE DEACETYLASE INHIBITION; EXPERIMENTAL INTRACEREBRAL HEMORRHAGE; MEDIATED OXIDATIVE INJURY; MOOD STABILIZER; BRAIN-INJURY; STROKE-ASSOCIATION; SIGNALING PATHWAY; TIN-MESOPORPHYRIN; TRANSGENIC MICE; NEUROTOXICITY;

D O I：

10.1016/j.neuint.2012.12.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

During hemorrhagic stroke induced by intracerebral hemorrhage (ICH), brain injury occurs from the deleterious actions of hemoglobin byproducts; induction of heme oxygenase-1 (HO-1) also plays a critical role in the neurotoxicity in ICH. Valproic acid (VPA), which is a commonly used drug in the treatment of epilepsy, has been reported to have neuroprotective effects against various neuronal insults including ischemic stroke. We investigated the effect of VPA on HO-1-mediated neurotoxicity in an experimental model of ICH. We investigated the effects of VPA on HO-1 protein in primary cortical neurons: (1) the expression levels of HO-1 mRNA and protein measured by RT-PCR and Western blotting; (2) the cell viability and ROS generation by MIT reduction assay and ROS measurement; (3) the signal pathway regulated by VPA using IP-Western blotting; (4) the effects of VPA on hemin-induced cell death by hemin microinjection and immunohistochemistry in vivo. VPA treatment partially blocked cell death induced by hemin, which is released from hemoglobin during ICH, both in rat primary cortical neurons and rat brain. Treatment of VPA significantly decreased the expression of HO-1 protein both in vitro and in vivo. Hemin treatment induced HO-1 protein expression and this was partially blocked by pretreatment with VPA, which might be mediated by increased ubiquitination and degradation of HO-1 via ERK1/2 and JNK activation in primary cortical neurons. Our results indicate that VPA inhibits hemin toxicity by downregulating HO-1 protein expression, and provide a therapeutic strategy to attenuate intracerebral hemorrhagic injury. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：240 / 250

页数：11

共 39 条

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