The overall aim of this proposal is to assess the participation of the complement system and other related plasma proteins in brain damage and vascular dementia caused by hypertension and/or cerebral vascular disease. The activation of the complement system results in the generation of biologically active peptides that are pro-inflammatory and cytotoxic and these include the anaphylatoxins, C3a, C4a and C5a; the opsonins C3b and C3bi and the membrane attack complex C5b-9.
The specific aims of the proposal are: (1) to assess the integrity of the blood-brain barrier (BBB) in hypertensive, atherosclerotic and hypertension-atherosclerotic monkeys by Evan's blue leakage from the circulation and by immunochemical and immunocytochemical analyses of brain tissue for plasma proteins; (2) to determine whether complement proteins are extravasated with other plasma proteins into the brain tissue and undergo activation following the disruption of the BBB; (3) circulation and co-localize with complement in the brain tissue; (4) to identify the specific cell types and histological localization of these cell types that immunostain for complement or plasma proteins that might activate the complement system also leak from the circulation and co- localize with complement in the brain tissue; (4) to identify the specific cell types and histological localization of these cell types that immunostain for complement or plasma proteins in the brain tissue; (5) to correlate the disruption of the BBB and leakage of biologically active proteins with the histopathological changes in the brain. Four groups of mature male Cynomolgus monkeys will be studied consisting of a (1) normal control group, (2) hypertensive group, (3) atherosclerotic group and (4) hypertensive and atherosclerotic group. This experimental design will permit the study by (1) Evans blue leakage from the proteins and (3) immunochemical analyses of brain extracts for plasma proteins. Complement activation following the disruption of the BBB also will be assessed using specific antibodies to complement activation products. For immunocytochemistry, the Avidin-Biotin immunoperoxidase method will be used qualitatively and the immunostaining of plasma proteins and complement. The breakdown of the BBB and associated brain damage also will be correlated with the neuropathologic findings in the eyes and brain of the animals as well as the behavioral changes in the animals and other clinical findings. The proposed studies should enhance the understanding of the pathogenesis of brain damage and vascular dementia associated with hypertension and ischemic cerebral vascular disease.
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