Thromboembolic mechanisms play a major role in the pathogenesis of transient ischemic attacks and acute stroke. Over the past several years, we have documented the acute and evolving histopathological, blood-brain barrier, hemodynamic and neurochemi calabnormalities generated by photochemically induced nonocclusive common carotid artery thrombosis (CCAT) in rats. This well- controlled animal model generates multiple injury processes that we believe mimic the important features of human stroke. Nor-phological and autoradiographic evidence for transient platelet embolization leading to complex patterns of evolving microvascular, neuronal and inflammatory changes have been obtained. Cerebral blood flow studies have documented heterogeneous patterns of altere blood flow that parallel the hemodynamic abnormalities seen in acute stroke patients. Based on Previous studies, in addition to new data summarized in this application, we hypothesize that CCAT leads to a cascade of microvascular and neuronal changes that require clarification before rational therapeutic strategies can be developed A new double-label autoradiographic strategy will be used to investigate regionally- specific interrelationships between platelet emboli and hemodynamic abnormalities. Neurochemical studies will determine whether plasma levels of vasoactive and/or neuroactive substances increase after CCAT and whether humoral factors gain accessto- extravascular pools via a leaky blood-brain barrier. We will determine whether hemodynamic reserve is restricted after CCAT and whether this condition predisposes the brain to secondary fur. Evidence for acute vascular endothelial stress after transient platelet embolization will be obtained using heat shock protein-72 immunocyto- chemistry combined with electron microscopy. The importance of inflammatory responses on thrombotic outcome will be investigated by documenting patterns of microglial activation and the upregulation of endothelial adhesion molecule-I. At present, there is an incomplete understanding of how thromboembolic processes may affect brain structure and function and how these events might predispose the brain to subsequent injury. Thus, our overall goal is to use our thromboembolic model combined with well established histopathological, hemodynamic and neurobehavioral endpoints, to critical investigate the pathobiology of embolic stroke so that novel pathways may be targeted therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027127-08
Application #
2431170
Study Section
Neurology A Study Section (NEUA)
Program Officer
Jacobs, Tom P
Project Start
1990-08-01
Project End
2000-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Lozano, J Diego; Abulafia, Denise P; Danton, Gary H et al. (2007) Characterization of a thromboembolic photochemical model of repeated stroke in mice. J Neurosci Methods 162:244-54
Bramlett, Helen M; Dietrich, W Dalton (2004) Pathophysiology of cerebral ischemia and brain trauma: similarities and differences. J Cereb Blood Flow Metab 24:133-50
Danton, Gary H; Dietrich, W Dalton (2004) The search for neuroprotective strategies in stroke. AJNR Am J Neuroradiol 25:181-94
Urrea, Carlos; Danton, Gary H; Bramlett, Helen M et al. (2004) The beneficial effect of mild hypothermia in a rat model of repeated thromboembolic insults. Acta Neuropathol (Berl) 107:413-20
Danton, Gary H; Dietrich, W Dalton (2003) Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62:127-36
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
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
Katz, L M; Lotocki, G; Wang, Y et al. (2001) Regulation of caspases and XIAP in the brain after asphyxial cardiac arrest in rats. Neuroreport 12:3751-4
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

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