Diffusion MRI (D-MRI) studies from our group and others have described the propagation, reversal and delayed recurrence of cellular edema in the penumbra during temporary focal cerebral ischemia that is a variable response to the site and duration of occlusion and reperfusion. The overall hypothesis of this continuation proposal are 1) that propagation of necrosis in peri-focal regions occurs due to recurrent spreading depression (SD) and progressive but potentially reversible ischemic depolarization (ID), 2) that deterioration of the penumbra can be monitored by D-MRI and by decreased protein synthesis (PS), 3) that injury in the penumbra can be aggravated by oxidative stress, 4) that propagation of necrosis in the penumbra can be prevented by treatments like hypothermia and glutamate receptor antagonists 5) and that delayed ischemic neuronal damage (IND) in the penumbra can be predicted by failure of recovery of protein synthesis. The planned experiments will use advanced magnetic resonance imaging methods, D-MRI and perfusion-MRI (P-MRI), that are currently available for clinical application to identify and localize dynamic patterns of cellular edema and vascular perfusion alterations in the penumbra during the evolution of a stroke; and to correlate these with EEG, histological outcome, autoradiographic cerebral blood flow and local protein synthesis rates, and induction of specific genes. The carotid endovascular suture model developed in our laboratory for study of reversible MCA occlusion in both rats and mice will be utilized. The induction of SD and ID by potassium chloride or ischemia will be correlated with induction of c-fos immediate early gene and D-MRI; regions in the penumbra where IND occurs will be correlated with regions of HSP70 stress gene induction and regions of decreased protein synthesis. Regions that eventually infarct will be detected histologically and compared with the time course of early D-MRI and P-MRI alterations. Experiments will determine whether the signals detected by D-MRI and P-MRI will correlate with regions of eventual infarction, or with regions of penumbra with decreased protein synthesis of IND. The dynamic effects on the propagation of edema during ischemia and reperfusion will be investigated following treatment with hypothermia and glutamate receptor antagonists, and in transgenic mice with overexpression of superoxide dismutase. Results will determine whether the extent and duration of decrease of protein synthesis predicts the distribution and fate of the penumbra. Methods will be developed to identify the """"""""penumbra"""""""" around an infarction in the living brain which may be rescued by therapeutic intervention.
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