The major goal of this project is to document patterns of platelet deposition, blood flow and edema during the development of focal thrombotic stroke, and the effects of prophylactic agents on mitigating or inhibiting thrombus formation in brain vasculature. A secondary goal is to determine whether lipid peroxidation is associated with thrombotic stroke, and to characterize the distribution of lipid peroxides in parenchyma and endothelium of the affected tissue zone and correlate this with morphological indices as the stroke progresses. The proposed studies will utilize our recently characterized model of reproducible focal cerebral infarction precipitated by photochemically induced thrombosis of cortical vasculature, in rats injected systemically with the potent photosensitizing dye Rose Bengal. The progression of thrombosis will be represented by platelets radiolabeled with IIIindium, and local cerebral blood flow will be evaluated by 14C-labeled iodoantipyrine imaging. Microvascular occlusion will be visualized directly by carbon-black perfusion. The effect on these parameters of agents known to mitigate thrombosis of single vessels in vivo will be evaluated in the present context of a network of occluded vasculature; such agents include calcium channel antagonists (nimodipine, nifedipine, verapamil), antiplatelet drugs (aspirin, indomethacin, prostacyclin), free radical scavengers (ethanol, dimethylsufoxide, glycerol) and the clot-specific fibrinolytic agent, tissue plasminogen activator (t-PA). Enhancement of the effect of t-PA by prior administration of lys-plasminogen will be tested also. The hypothesis that lipid peroxidation inhibits the recovery of tissue compromised by ischemia can be studied if lipid peroxide formation can be induced in specific tissue zones. In this model it is likely that platelet adhesion and subsequent aggregation are stimulated by photochemical peroxidation of endothelial lipids. Owing to the reproducible progression of blood flow deficit in the photoinduced lesion, the present model may facilitate stable conditions for lipid peroxidation, observable as conjugated dienes, in the parenchyma as well. The relative content (predicted to be low) of endothelial lipid peroxides, and the efficiency of photochemical induction of endothelial defects will be determined by similar experiments conducted with endothelial cells in culture. The proposed work enables rigorous study of the thrombotic process and its mitigation under well-controlled condition in brain microvessels, with consequent benefit to potential stroke patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS023244-01
Application #
3406506
Study Section
Neurology A Study Section (NEUA)
Project Start
1985-08-01
Project End
1988-07-31
Budget Start
1985-08-01
Budget End
1986-07-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33101
Danton, Gary H; Prado, Ricardo; Truettner, Jessie et al. (2002) Endothelial nitric oxide synthase pathophysiology after nonocclusive common carotid artery thrombosis in rats. J Cereb Blood Flow Metab 22:612-9
Watson, Brant D; Prado, Ricardo; Veloso, Alexander et al. (2002) Cerebral blood flow restoration and reperfusion injury after ultraviolet laser-facilitated middle cerebral artery recanalization in rat thrombotic stroke. Stroke 33:428-34
Danton, Gary H; Prado, Ricardo; Watson, Brant D et al. (2002) Temporal profile of enhanced vulnerability of the postthrombotic brain to secondary embolic events. Stroke 33:1113-9
Dietrich, W D; Truettner, J; Prado, R et al. (2000) Thromboembolic events lead to cortical spreading depression and expression of c-fos, brain-derived neurotrophic factor, glial fibrillary acidic protein, and heat shock protein 70 mRNA in rats. J Cereb Blood Flow Metab 20:103-11
Dietrich, W D; Prado, R; Pravia, C et al. (1999) Delayed hypovolemic hypotension exacerbates the hemodynamic and histopathologic consequences of thromboembolic stroke in rats. J Cereb Blood Flow Metab 19:918-26
Dietrich, W D; Danton, G; Hopkins, A C et al. (1999) Thromboembolic events predispose the brain to widespread cerebral infarction after delayed transient global ischemia in rats. Stroke 30:855-61;discussion 862
Zhao, W; Ginsberg, M D; Prado, R et al. (1996) Depiction of infarct frequency distribution by computer-assisted image mapping in rat brains with middle cerebral artery occlusion. Comparison of photothrombotic and intraluminal suture models. Stroke 27:1112-7
Back, T; Ginsberg, M D; Dietrich, W D et al. (1996) Induction of spreading depression in the ischemic hemisphere following experimental middle cerebral artery occlusion: effect on infarct morphology. J Cereb Blood Flow Metab 16:202-13
Prado, R; Watson, B D; Zhao, W et al. (1996) L-arginine does not improve cortical perfusion or histopathological outcome in spontaneously hypertensive rats subjected to distal middle cerebral artery photothrombotic occlusion. J Cereb Blood Flow Metab 16:612-22
Belayev, L; Busto, R; Watson, B D et al. (1995) Post-ischemic administration of HU-211, a novel non-competitive NMDA antagonist, protects against blood-brain barrier disruption in photochemical cortical infarction in rats: a quantitative study. Brain Res 702:266-70

Showing the most recent 10 out of 55 publications