Totarol prevents neuronal injury in vitro and ameliorates brain ischemic stroke: Potential roles of Akt activation and HO-1 induction

被引：63

作者：

Gao, Yuanxue ^{[1
]}

Xu, Xiaojun ^{[1
]}

Chang, Sai ^{[1
]}

Wang, Yunjie ^{[1
]}

Xu, Yazhou ^{[1
]}

Ran, Siqi ^{[1
]}

Huang, Zhangjian ^{[2
]}

Li, Ping ^{[1
]}

Li, Jia ^{[3
]}

Zhang, Luyong ^{[1
]}

Saavedra, Juan M. ^{[4
]}

Liao, Hong ^{[1
]}

Pang, Tao ^{[1
,4
]}

机构：

[1] China Pharmaceut Univ, Jiangsu Key Lab Drug Screening, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China

[2] China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Nanjing 210009, Jiangsu, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[4] Georgetown Univ, Med Ctr, Dept Physiol & Pharmacol, Washington, DC 20057 USA

来源：

TOXICOLOGY AND APPLIED PHARMACOLOGY | 2015年 / 289卷 / 02期

基金：

中国国家自然科学基金;

关键词：

Totarol; HO-1; Akt; Neuroprotection; Stroke; GLUTAMATE-INDUCED NEUROTOXICITY; CEREBRAL-ARTERY OCCLUSION; RAT CEREBELLAR NEURONS; KAPPA-B EXPRESSION; UP-REGULATED PAKT; OXIDATIVE STRESS; HEME OXYGENASE; MOLECULAR-MECHANISMS; NUTRIENT DEPRIVATION; NRF2-KEAP1; PATHWAY;

D O I：

10.1016/j.taap.2015.10.001

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The natural product totarol, a phenolic diterpenoid and a major constituent isolated from the sap of Podocarpus totara, has been reported to have a potent antimicrobial activity. In this study, we determined whether totarol possessed an additional neuroprotective activity in vitro and in vivo. We found that totarol prevented glutamate- and oxygen and glucose deprivation-induced neuronal death in primary rat cerebellar granule neuronal cells and cerebral cortical neurons. Totarol increased Akt and GSK-3 beta phosphorylation, Nrf2 and heme oxygenase-1 (HO-1) protein expressions and suppressed oxidative stress by increasing GSH and SOD activities. The PI3K/Akt inhibitor LY294002 prevented totarol neuroprotective effect by suppressing the totarol-induced changes in HO-1 expression and the activities of GSH and SOD. The HO-1 inhibitor ZnPPIX also prevented totarol-increased GSH and SOD activities. In a model of acute cerebral ischemic injury in Sprague-Dawley rats, produced by occlusion of the middle cerebral artery for 2 h followed by 22 h or 46 h of reperfusion, totarol significantly reduced infarct volume and improved the neurological deficit. In this model, totarol increased HO-1 expression and the activities of GSH and SOD.These observations suggest that totarol may be a novel activator of the Akt/HO-1 pathway protecting against ischemic stroke through reduction of oxidative stress. (C) 2015 Elsevier Inc. All rights reserved.

引用

页码：142 / 154

页数：13

共 63 条

[1] INVITED REVIEW - TOTAROL - A NONCONVENTIONAL DITERPENOID [J].