Cerebrovascular disease, or stroke is the third leading cause of death in the United States and a major cause of disability. At the present time there is no treatment of proven efficacy in treating or ameliorating strokes. Recent evidence has accumulated suggesting that specific antagonism of postsynaptic glutamate receptors, especially the N-methyl-D-aspartate (NMDA) receptor protects neurons from hypoxic or ischemic injury. Over the last three years my laboratory has shown that dextromethorphan (DM), an NMDA antagonist, and its major metabolite, dextrorphan (DX), have a significant protective effect against focal cerebral ischemia in our rabbit model when given prior to the onset of ischemia and also when administered in a delayed fashion one hour after the onset of ischemia. The purpose of this research is to further elucidate the precise conditions of focal cerebral ischemia that will respond to treatment with DM or DX and to delineate the mechanism of protection. Focal cerebral ischemia will be produced in anesthetized rabbits by transorbital, clip occlusion of the internal carotid artery, anterior cerebral artery and middle cerebral artery. The degree of cerebral ischemia will be determined using electrophysiological (somatosensory evoked potentials), radiological (magnetic resonance imaging), histological and behavioral criteria. Experiments will characterize the dose response curve for both drugs regarding cerebral protection and toxicity, will determine the relative roles of loading versus maintenance drug therapy, and will define the maximal delay after ischemia that these drugs can be administered and still demonstrate neuroprotection. Regional cerebral blood flow will be measured using two techniques (laser Doppler flowmetry and radioactive microspheres to determine whether the drugs' neuroprotective effects and regional selectivity are due to changes in blood flow. The efficacy of these agents will also be examined over a longer period of time (24 hours) and brain levels will be correlated with plasma levels. DM and DX have already been clinically tested and are known to be relatively free of side effects. If the studies outlined in this proposal confirm the benefit of DM or DX in protecting against cerebral ischemia, the implications for treatment of humans with stroke could be profound in terms of reducing neurologic morbidity or mortality. The results from the proposed project will expedite the planning and execution of a clinical study.
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