The overall objectives of this proposal are to (l) define the structural changes initiated in the brain by an arterial occlusion, and (2) examine the contribution that reperfusing an area of "evolving focal cerebral ischemia" may have on either decreasing the histologic damage initiated by the arterial occlusion or inducing hemorrhagic complications. "Evolving focal ischemia" describes the series of structural abnormalities set in motion by an arterial occlusion. The procedures to be applied allow to occlude and re-open a middle cerebral artery (MCA) without opening the skull; this is deemed essential in order to maintain intracranial pressure unaffected by anything but focal brain ischemia. The methods to evaluate the tissue alterations include in-vivo Nuclear Magnetic Resonance Imaging (MRI) and detailed microscopy of the cerebral microvasculature and neuronal/astrocytic components to determine: (a) patency of microvessels, (b) integrity of the blood-brain barrier to macromolecules, (c) timing and topographic distribution of microvascular plugging by red blood cells, fibrin, platelets, or combinations of these, (d) earliest arrival and endothelial apposition of polymorphonuclear leukocytes, and (e) definition of the parenchymal changes. These alterations will be evaluated as a function of the elapsed after occluding the parent artery and degree or type of injury to the neurons/astrocytes located in the territory of the occluded artery. Spontaneous bleeding into an incipient brain infarct is not an uncommon complication but, the mechanisms and, the prevention of this event are poorly understood(6,42). Two general hypotheses will be tested: (1) The brain lesion initiated by an arterial occlusion evolves through two stages: acute ischemic injury begins within minutes and is followed by delayed changes (or infarct); these two stages are separated from one another by an as yet undetermined number of hours; (2) Reperfusing the ischemic territory during the period of acute ischemic injury will improve the histologic abnormalities, whereas reperfusion during the period of delayed changes will result in intracerebral hemorrhage. Mechanistic hypothesis: Bleeding, as a complication of a brain infarct, is a consequence of widespread endothelial necrosis (affecting the microvasculature); factors that enhance bleeding during the period of microvascular necrosis include reperfusion. The presence of abundant neutrophils in the area of focal ischemia contributes to the endothelial necrosis(52,92) and therefore to the induction of brain hemorrhage. In view of the current interest in developing prompt treatment of "ischemic stroke" with both thrombolytic agents and endarterectomy of stenotic arteries, the results of these experiments may have significant impact in the future management of acute ischemic stroke.