FOCAL CEREBRAL ISCHEMIA--PATHOPHYSIOLOGY, ACUTE THERAPY, RECOVERY OF FUNCTION

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Biochemical and ionic events within the first few hours after focal vascular occlusion critically determine the extent and intensity of cell death and may provide critical stimuli to subsequent functional rearrangement and recovery of the brain. This project employs an extensively characterized, minimally invasive model of photothrombotic middle cerebral artery (MCA) occlusion -a model relevant to human thromboembolic stroke. A major aim is to characterize factors responsible for engendering acute bioenergetic stress in the ischemic penumbra, including excessive local metabolism/blood flow uncoupling and repeated ischemic depolarizations. The relationship of these processes to the local release of glutamate and other neurotransmitters, and to the local production of oxygen radicals, will be explored. Analysis of local cytoskeletal proteolysis and light- and electron microscopic histopathology will provide structural correlates. Modulation of acute metabolic events in the penumbra will be achieved by inducing additional depolarizations, by mild hyperthermia or hypothermia, by early partial reperfusion, and by agents affecting the glutamate system. The second major aim is to determine how these acute events influence subsequent patterns of functional recovery, as assessed by a neurobehavioral battery, by glucose-metabolic activation of affected forelimb areas, and by the expression of messenger RNA and protein for neurotrophin growth factors and their trk receptors. We shall discern whether acute protective strategies might aid or paradoxically hinder later functional reorganization, and we shall assess the mechanisms underlying the enhancement of functional recovery by amphetamine coupled with symptom- relevant experience. The project makes extensive use of novel three- dimensional autoradiographic image-averaging strategies in conjunction with neurobehavior, in situ hybridization, immunohistochemistry and morphologic methods.