The overall objectives of this proposal are to further examine the mechanism of formation of microvascular occlusions found in the lenticulostriate (LSA) territory and their contribution to cerebral ischemia following acute middle cerebral artery (MCA) occlusion and reperfusion. The hypotheses to be tested state i) that such occlusions result from the adherence of PMN leukocytes to endothelial receptors in the LSA microvasculature, platelet-associated fibrin formation, and/or thrombosis, and ii) that novel, well-characterized reagents which inhibit leukocyte adherence/activation, platelet-fibrin association, or coagulation will increase microvascular patency, decrease infarction volume, and improve neurological outcome. PMN leukocytes and fibrin found in the microcirculation following MCA occlusion and reperfusion in the primate acute focal ischemia model suggest a pathogenesis for the """"""""no-reflow"""""""" phenomenon. Measures which reduce the extent of this phenomenon may reduce the region of focal cerebral ischemia and improve neurological recovery. Heretofore, this concept has not been directly testable. Strategies to alter post-focal ischemia/reperfusion (I/R) microvascular occlusion formation and the neurological consequences of these interventions will be developed in three stages: i) mechanisms underlying microvascular occlusion formation will be examined by immunohistochemical methods in MCA reperfusion experiments; ii) modulation/inhibition of microvascular occlusions will be evaluated with novel techniques in short- term experiments which achieve maximum vascular patency; and iii) the ability of approaches developed in i) and ii) to also decrease infarction volume and improve functional outcome will be assessed in long-term experiments in the primate model. Outcomes in i) and ii) will be quantitated by video-imaging microscopy of microvascular patency, occlusion, and integrity using proven tissue techniques and data acquisition methods. The relevance of post-I/R microvascular events to local cerebral blood flow disturbances will be confirmed by magnetic resonance imaging and neuropathology. In view of clinical studies demonstrating successful cerebral arterial recanalization, the approaches in this proposal may have significant consequences for future acute stroke patient management and outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS026945-11S1
Application #
6149391
Study Section
Neurology A Study Section (NEUA)
Program Officer
Jacobs, Tom P
Project Start
1988-12-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2001-04-30
Support Year
11
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Del Zoppo, Gregory J (2013) Toward the neurovascular unit. A journey in clinical translation: 2012 Thomas Willis Lecture. Stroke 44:263-9
Muldoon, Leslie L; Alvarez, Jorge I; Begley, David J et al. (2013) Immunologic privilege in the central nervous system and the blood-brain barrier. J Cereb Blood Flow Metab 33:13-21
del Zoppo, Gregory J; Izawa, Yoshikane; Hawkins, Brian T (2013) Hemostasis and alterations of the central nervous system. Semin Thromb Hemost 39:856-75
del Zoppo, Gregory J (2013) Plasminogen activators and ischemic stroke: conditions for acute delivery. Semin Thromb Hemost 39:406-25
del Zoppo, Gregory J; Frankowski, Harald; Gu, Yu-Huan et al. (2012) Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab 32:919-32
Frankowski, Harald; Gu, Yu-Huan; Heo, Ji Hoe et al. (2012) Use of gel zymography to examine matrix metalloproteinase (gelatinase) expression in brain tissue or in primary glial cultures. Methods Mol Biol 814:221-33
del Zoppo, Gregory J; Sharp, Frank R; Heiss, Wolf-Dieter et al. (2011) Heterogeneity in the penumbra. J Cereb Blood Flow Metab 31:1836-51
Osada, Takashi; Gu, Yu-Huan; Kanazawa, Masato et al. (2011) Interendothelial claudin-5 expression depends on cerebral endothelial cell-matrix adhesion by ?(1)-integrins. J Cereb Blood Flow Metab 31:1972-85
del Zoppo, Gregory J (2010) Acute anti-inflammatory approaches to ischemic stroke. Ann N Y Acad Sci 1207:143-8
del Zoppo, Gregory J (2010) Plasminogen activators in ischemic stroke: introduction. Stroke 41:S39-41

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