Ann. N.Y. Acad. Sci. 993: 276–286 (2003). © 2003 New York Academy of Sciences. Potential Mechanism by Which Resveratrol, a Red Wine Constituent, Protects Neurons HEAN ZHUANG, YUN-SOOK KIM, RAYMOND C. KOEHLER, AND SYLVAIN DORÉ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA ABSTRACT: Polyphenolic compounds, such as resveratrol, are naturally present at high concentration in grape skin, seeds, and red wine. Resveratrol is present in cis and trans isoforms and the major trans isomer is the biologically active one. Epidemiologic studies have revealed a reduced incidence of cardiovascular risk associated with consumers of red wine; this has been popularized as the French paradox. Resveratrol has been shown to have significant antioxidant properties in a variety of in vitro and in vivo models. It can reduce ischemic damage in heart ischemia reperfusion injury and also in brain ischemia/reper- fusion in rodent models. Due to the high rate of oxygen consumption in the brain, and especially low levels of antioxidant defense enzymes, this organ is particularly susceptible of free radical damage. Most of the protective biologi- cal actions associated with resveratrol have been associated with its intrinsic radical scavenger properties. We have investigated the possibility of other indi- rect pathways by which resveratrol can exert its neuroprotective abilities. We have specifically tested whether heme oxygenase neuroprotective enzyme could be stimulated after resveratrol treatment. Using primary neuronal cultures, resveratrol was able to significantly induce heme oxygenase 1, whereas vehicle control showed no effect. No detectable toxicity was quantified. It is well estab- lished that after stroke significant levels of intracellular heme levels increase. The source of free heme comes mainly from several heme-containing enzymes. Heme (iron-protoporphyrin IX) is a pro-oxidant and its rapid degradation by heme oxygenase is believed to be protective. Moreover, the generation of heme metabolites can also have their own intrinsic cellular properties. All together, increased heme oxygenase activity by resveratrol is a unique pathway by which this compound can exert its neuroprotective actions. KEYWORDS: Alzheimer’s disease; antioxidant; cerebral ischemia; free radical; iron; oxidative stress; polyphenol; neurodegeneration; stroke ABBREVIATIONS: AD Alzheimer’s disease BV biliverdin BR bilirubin CO carbon monoxide CP 450 R cytochrome P450 reductase ER endoplasmic reticulum Fe iron HO heme oxygenase MTT 3-(4,5-dimethylthiazol-2yl)2,5-diphenyl tetrazolium bromide Address for correspondence: Sylvain Doré, Ph.D., Johns Hopkins University, School of Medicine, Dept. of Anesthesiology and Critical Care Medicine, 600 N. Wolfe Street, (Blalock 1404A), Baltimore, MD 21287, USA. Voice: 410-614-4859; fax: 410-955-7165. sdore@jhmi.edu