title: 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.affiliation: Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Ning
authors.initials: N
authors.lastname: Xia
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Lianjun
authors.initials: L
authors.lastname: Guo
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Förstermann
authors.forename: Huige
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D013312:Stress, Physiological / Q000187:drug effects*; D014315:Triterpenes / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D000094062:Betulinic Acid
chemical_list: D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger; D026361:Reactive Nitrogen Species; D014315:Triterpenes; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D000094062:Betulinic Acid