Cerebral vasospasm after subarachnoid hemorrhage (SAH) remains the greatest limitation to successful post-operative management of aneurysmal stroke. Despite intensive study, the basic mechanisms leading to """"""""irreversible"""""""" chronic cerebroarterial constriction in response to subarachnoid (SA) blood clot remain unclear. This project seeks, as its long-term objective, intervention against a major cause of morbidity and mortality after aneurysm rupture. It has been long believed that erythrocytes in the SA clot are crucial to the development of cerebral vasospasm. Recent work in the canine model supports this idea and has led to a specific hypothesis for the mechanisms of human cerebral vasospasm. Testing of that hypothesis is the specific aim of this proposal. Central to the hypothesis is our finding that human erythrocytes incubated in vitro under conditions like those of the SA clot do not lyse rapidly, but become progressively denatured on a time-scale compatible with the onset of clinical pathology. Upon exposure to plasma complement proteins, such """"""""aged"""""""" erythrocytes initiate the """"""""alternate"""""""" pathway of complement activation, leading to formation of """"""""membrane attack complex"""""""" and their own hemolysis. Additional actions of activated complement include stimulation of inflammatory infiltration and increased permeability of the blood-brain barrier. The proposed in vitro work will examine whether this finding is a general feature of human and canine erythrocytes. The canine model will be used to verify that denatured SA erythrocytes promote by complement protein activation two major components of cerebral vasospasm: inflammation and hemolysis. The role of local extravasation of plasma protein into the SA clot, which would then lead to rapid complement-induced hemolysis, will be examined by immunohistochemical and protein marker studies. The time- course of SA erythrocyte denaturation may well account for the clinical hallmark of cerebral vasospasm: delayed onset after SAH. The proposed studies represent a departure from previous efforts which emphasized vasoactive substances arising in the SA clot.
By aimi ng at prevention of rapid SA erythrocyte lysis, a whole cycle of threatening events may be prevented.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL044554-01
Application #
3363365
Study Section
Neurology A Study Section (NEUA)
Project Start
1990-07-01
Project End
1993-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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Yokota, M; Peterson, J W; Kaoutzanis, M C et al. (1995) Protein kinase C and diacylglycerol content in basilar arteries during experimental cerebral vasospasm in the dog. J Neurosurg 82:834-40
Yamakawa, K; Peterson, J W; Sibilia, R et al. (1995) Effect of vasoconstrictor agents on diacylglycerol content of normal and vasospastic canine basilar arteries in vitro. Neurosurgery 36:789-96
Kaoutzanis, M; Yokota, M; Sibilia, R et al. (1993) Neurologic evaluation in a canine model of single and double subarachnoid hemorrhage. J Neurosci Methods 50:301-7
Yokota, M; Peterson, J W; Kaoutzanis, M et al. (1992) Immunohistochemical distribution of protein kinase C isozymes is differentially altered in ischemic gerbil hippocampus. Brain Res 587:123-9