PHOTOINDUCED THROMBOTIC STROKE--MECHANISMS AND THERAPY

  • Watson, Brant D., (PI)

Project: Research project

Description

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.
StatusFinished
Effective start/end date8/1/8512/31/04

Funding

  • National Institutes of Health: $238,585.00
  • National Institutes of Health
  • National Institutes of Health: $316,205.00
  • National Institutes of Health
  • National Institutes of Health: $258,053.00
  • National Institutes of Health: $221,740.00
  • National Institutes of Health
  • National Institutes of Health: $325,692.00
  • National Institutes of Health: $234,142.00
  • National Institutes of Health: $345,527.00
  • National Institutes of Health: $335,462.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $148,767.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Stroke
Thrombosis
Lipid Peroxidation
Reperfusion Injury
Nitric Oxide
Lipid Peroxides
Reperfusion
Middle Cerebral Artery
Rose Bengal
Lipids
Cerebrovascular Circulation
Brain
Argon
Tissue Plasminogen Activator
Middle Cerebral Artery Infarction
Observation
Fibrinolytic Agents
Edema
Dye Lasers
Leeches

ASJC

  • Medicine(all)
  • Neuroscience(all)