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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS031631-01A2
Application #
2269577
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1994-06-20
Project End
1999-05-31
Budget Start
1994-06-20
Budget End
1995-05-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Henry Ford Health System
Department
Pathology
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Liu, K F; Li, F; Tatlisumak, T et al. (2001) Regional variations in the apparent diffusion coefficient and the intracellular distribution of water in rat brain during acute focal ischemia. Stroke 32:1897-905
Li, F; Liu, K F; Silva, M D et al. (2000) Transient and permanent resolution of ischemic lesions on diffusion-weighted imaging after brief periods of focal ischemia in rats : correlation with histopathology. Stroke 31:946-54
Garcia, J H (1999) [Atherosclerosis, cerebral ischemia and cellular inflammation] Rev Neurol 28:1009-12
Pantoni, L; Garcia, J H (1997) Cognitive impairment and cellular/vascular changes in the cerebral white matter. Ann N Y Acad Sci 826:92-102
Garcia, J H; Liu, K F; Ye, Z R et al. (1997) Incomplete infarct and delayed neuronal death after transient middle cerebral artery occlusion in rats. Stroke 28:2303-9; discussion 2310
Pantoni, L; Garcia, J H (1997) Pathogenesis of leukoaraiosis: a review. Stroke 28:652-9
Garcia, J H; Lassen, N A; Weiller, C et al. (1996) Ischemic stroke and incomplete infarction. Stroke 27:761-5
Pantoni, L; Garcia, J H; Gutierrez, J A (1996) Cerebral white matter is highly vulnerable to ischemia. Stroke 27:1641-6;discussion 1647
Garcia, J H; Liu, K F; Bree, M P (1996) Effects of CD11b/18 monoclonal antibody on rats with permanent middle cerebral artery occlusion. Am J Pathol 148:241-8
Garcia, J H; Khang-Loon, H (1996) Carotid atherosclerosis. Definition, pathogenesis, and clinical significance. Neuroimaging Clin N Am 6:801-10

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