title: Sustained neurological recovery induced by resveratrol is associated with angioneurogenesis rather than neuroprotection after focal cerebral ischemia.
abstract: According to the French paradox, red wine consumption reduces the incidence of vascular diseases even in the presence of highly saturated fatty acid intake. This phenomenon is widely attributed to the phytoalexin resveratrol, a red wine ingredient. Experimental studies suggesting that resveratrol has neuroprotective properties mostly used prophylactic delivery strategies associated with short observation periods. These studies did not allow conclusions to be made about resveratrol's therapeutic efficacy post-stroke. Herein, we systematically analyzed effects of prophylactic, acute and post-acute delivery of resveratrol (50mg/kg) on neurological recovery, tissue survival, and angioneurogenesis after focal cerebral ischemia induced by intraluminal middle cerebral artery occlusion in mice. Over an observation period of four weeks, only prolonged post-acute resveratrol delivery induced sustained neurological recovery as assessed by rota rod, tight rope and corner turn tests. Although prophylactic and acute resveratrol delivery reduced infarct volume and enhanced blood-brain-barrier integrity at 2 days post-ischemia by elevating resveratrol's downstream signal sirtuin-1, increasing cell survival signals (phosphorylated Akt, heme oxygenase-1, Bcl-2) and decreasing cell death signals (Bax, activated caspase-3), a sustained reduction of infarct size on day 28 was not observed in any of the three experimental conditions. Instead, enhanced angiogenesis and neurogenesis were noted in animals receiving post-acute resveratrol delivery, which were associated with elevated concentrations of GDNF and VEGF in the brain. Thus, sustained neurological recovery induced by resveratrol depends on successful brain remodeling rather than structural neuroprotection. The recovery promoting effect of delayed resveratrol delivery opens promising perspectives for stroke therapy.
authors: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany.
authors: Dirk M
authors: DM
authors: Hermann
authors: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany; Hotchkiss Brain Institute, Libin Cardiovascular Institute and the Department of Physiology & Pharmacology, University of Calgary, AB, Canada.
authors: Anil
authors: A
authors: Zechariah
authors: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany.
authors: Britta
authors: B
authors: Kaltwasser
authors: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany; Division of Neurosurgery, St. Michael's Hospital, Keenan Research Center for Biomedical Science and the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors: Bert
authors: B
authors: Bosche
authors: Istanbul Medipol University, Regenerative and Restorative Medical Research Center, Istanbul, Turkey.
authors: Ahmet B
authors: AB
authors: Caglayan
authors: Istanbul Medipol University, Regenerative and Restorative Medical Research Center, Istanbul, Turkey.
authors: Ertugrul
authors: E
authors: Kilic
authors: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany; Istanbul Medipol University, Regenerative and Restorative Medical Research Center, Istanbul, Turkey. Electronic address: thorsten.doeppner@uk-essen.de.
authors: Thorsten R
authors: TR
authors: Doeppner
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020127:Recovery of Function; D000077185:Resveratrol; D045442:Rotarod Performance Test; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000008:administration & dosage*; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*
chemical_list: D013267:Stilbenes; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Angiogenesis; Cerebral ischemia; Neurogenesis; Neuroprotection; Neuroregeneration; Stroke