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

Abstract

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-3β 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 2h 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.

• Authors: Yuanxue Gao, Xiaojun Xu, Sai Chang, Yunjie Wang, Yazhou Xu, Siqi Ran, Zhangjian Huang, Ping Li, Jia Li, Luyong Zhang, Juan M Saavedra, Hong Liao, Tao Pang
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 289 Issue 2 Pg. 142-54 (Dec 01 2015) ISSN: 1096-0333 [Electronic] United States
• PMID: 26440581 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Abietanes
• Antioxidants
• Diterpenes
• Excitatory Amino Acid Agonists
• NF-E2-Related Factor 2
• Neuroprotective Agents
• Nfe2l2 protein, rat
• Glutamic Acid
• totarol
• Heme Oxygenase (Decyclizing)
• Hmox1 protein, rat
• Superoxide Dismutase
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• Glutathione
• Glucose

Topics

• Abietanes
• Animals
• Antioxidants (pharmacology)
• Brain (drug effects, enzymology, pathology)
• Cell Death (drug effects)
• Cell Hypoxia
• Cells, Cultured
• Disease Models, Animal
• Diterpenes (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Enzyme Induction
• Excitatory Amino Acid Agonists (toxicity)
• Glucose (deficiency)
• Glutamic Acid (toxicity)
• Glutathione (metabolism)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Heme Oxygenase (Decyclizing) (biosynthesis)
• Infarction, Middle Cerebral Artery (enzymology, pathology, prevention & control)
• Male
• NF-E2-Related Factor 2 (metabolism)
• Neurons (drug effects, enzymology, pathology)
• Neuroprotective Agents (pharmacology)
• Oxidative Stress (drug effects)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Superoxide Dismutase (metabolism)
• Time Factors