PATOS Research Center
Pathophysiology and Treatment of Stroke
Project – Dr. Klein
Extracts of the Ginkgo tree are widely sold as neuroprotective drugs, but their putative actions are not well characterized. This project evolved from studies in the last five years in which we characterized the effects of bilobalide , a major constituent of Ginkgo extracts. We observed breakdown of cellular membranes when brain slices were exposed to hypoxic or ischemic conditions. This toxic injury was completely blocked in the presence of low concentrations of bilobalide (1- 10 μ M). Further work indicated that bilobalide protects neurons by blocking the influx of chloride ; we and others demonstrated that this chloride influx is required for cellular toxicity to occur. We now test the hypothesis that blockade of chloride channels (e.g., by bilobalide) is a novel neuroprotective intervention in stroke. We already found that bilobalide reduces the infarct area following stroke and the formation of cellular edema (see picture below). As edema and concomitant increases of intracranial pressure are major determinants of patient survival after stroke, we hope to identify bilobalide as a lead structure to develop novel drugs. Importantly, bilobalide caused no visible toxic effects on sensoric and motoric function in animals and is well tolerated in humans.
Middle cerebral artery occlusion (MCAO) in the mouse. (Upper) The MCA was occluded by a thread inserted through the carotid artery. The animal was sacrificed after 24 hours, and brain tissue was cut and stained with tetrazolium salt. The non-stained (white) area indicates infarct size, the comparison of the two hemispheres gives an index of edema formation in the ischemic hemisphere. (Lower) This mouse was pretreated with bilobalide (10 mg/kg i.p.) 60 min prior to MCAO. Pretreatment with bilobalide reduced infarct area by 47% and edema formation by 70%.