This program of research is directed toward understanding links among pathophysiological events and histopathology after focal brain ischemia. The importance of this research stems from the fact that little is known of the natural history and consequences of the physiological changes produced by focal ischemia. This is due, in part, to the complex heterogeneities of pathophysiology and histopathology as these extend outward from the focal ischemic core. Also complicating such studies is that pathophysiology and histopathology are not static but vary with time as cells are incorporated into the ischemic core or into more normal regions. Focal ischemia is emphasized as a research target because: a) it is the most common of ischemic brain insults in patients; and b) there is hope that the neurological defects of focal ischemia may be limited if cells can be spared from being incorporated into the central, necrotic zone by halting the progression of pathophysiological changes in peri infarct tissues. Goals of this research are to test three broad hypotheses. Through specific experiments, our objective is to provide temporal and spatial definition to the consequences of focal ischemia produced by middle cerebral artery occlusion (MCAo) in rat brain. Concentration will be upon derangements produced by MCAo that are functional (changes in ion homeostasis as indicated by extracellular potassium ion activity; and metabolic activities as signalled by local blood flow, tissue oxygen tension and reduction/oxidation shifts of cytochrome oxidase) and histopathological (infarction or sporadic neuronal injury at locally demarcated sites). Hypotheses are: 1) ionic derangements occur in the ischemic core, and in zones of the penumbra and the peripenumbra after MCAo. These derangements are not static but vary with time after focal ischemia. Testing this hypothesis will give fundamental definition to potassium ion activity after MCAo; 2) spreading depression like depolarization waves promote loss of ion homeostasis and histopathology after focal ischemia; and 3) focal ischemia promotes residual metabolic dysfunction in penumbral areas. Within each hypothesis are specific protocols which will better resolve the progression of pathophysiological events after focal ischemia, and contribute to defining mechanisms by which the ischemic core may expand into penumbral regions or by which this expansion may be halted.
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