Betulinic acid protects against cerebral ischemia-reperfusion injury in mice by reducing oxidative and nitrosative stress.

Abstract

Increased production of reactive oxygen and nitrogen species following cerebral ischemia-reperfusion is a major cause for neuronal injury. In hypercholesterolemic apolipoprotein E knockout (ApoE-KO) mice, 2h of middle cerebral artery (MCA) occlusion followed by 22h of reperfusion led to an enhanced expression of NADPH oxidase subunits (NOX2, NOX4 and p22phox) and isoforms of nitric oxide synthase (neuronal nNOS and inducible iNOS) in the ischemic hemisphere compared with the non-ischemic contralateral hemisphere. This was associated with elevated levels of 3-nitrotyrosine, an indicator of peroxynitrite-mediated oxidative protein modification. Pre-treatment with betulinic acid (50mg/kg/day for 7days via gavage) prior MCA occlusion prevented the ischemia reperfusion-induced upregulation of NOX2, nNOS and iNOS. In parallel, betulinic acid reduced the levels of 3-nitrotyrosine. In addition, treatment with betulinic acid enhanced the expression of endothelial eNOS in the non-ischemic hemispheres. Finally, betulinic acid reduced infarct volume and ameliorated the neurological deficit in this mouse stroke model. In conclusion, betulinic acid protects against cerebral ischemia-reperfusion injury in mice. This is likely to result from a reduction of oxidative stress (by downregulation of NOX2) and nitrosative stress (by reduction of nNOS and iNOS), and an enhancement of blood flow (by upregulation of eNOS).

• Authors: Qing Lu, Ning Xia, Hui Xu, Lianjun Guo, Philip Wenzel, Andreas Daiber, Thomas Münzel, Ulrich Förstermann, Huige Li
• Journal: Nitric oxide : biology and chemistry (Nitric Oxide) Vol. 24 Issue 3 Pg. 132-8 (Apr 30 2011) ISSN: 1089-8611 [Electronic] United States
• PMID: 21292018 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Pentacyclic Triterpenes
• RNA, Messenger
• Reactive Nitrogen Species
• Triterpenes
• 3-nitrotyrosine
• Tyrosine
• Nitric Oxide Synthase
• NADPH Oxidases
• Betulinic Acid

Topics

• Animals
• Brain (metabolism)
• Brain Ischemia (prevention & control)
• Male
• Mice
• Mice, Knockout
• NADPH Oxidases (genetics, metabolism)
• Nitric Oxide Synthase (genetics, metabolism)
• Oxidative Stress
• Pentacyclic Triterpenes
• RNA, Messenger (metabolism)
• Reactive Nitrogen Species (metabolism)
• Reperfusion Injury (prevention & control)
• Stress, Physiological (drug effects)
• Triterpenes (pharmacology)
• Tyrosine (analogs & derivatives, genetics, metabolism)
• Betulinic Acid