Rasmussen's syndrome (RS) is a rare neurodegenerative disease of childhood in which a single cerebral hemisphere undergoes progressive destruction. The disease is characterized by gradual loss of functions sub-served by the involved hemisphere as well as severe epileptic seizures. During the current funding period, study of an animal model of RS and of brain tissue excised from children with RS provided evidence that inappropriate activation of complement may contribute to the disease. In particular, immunocytochemical evidence of membrane attack complex formation on neurons in RS brains was obtained. Despite evidence of membrane attack complex immunoreactivity in RS brains and in several neurodegenerative diseases including Alzheimer's, whether inappropriate activation of complement in mammalian brain exerts any deleterious effects is unknown. We have obtained preliminary evidence that inappropriate activation of complement, in particular the membrane attack complex, produces seizures and cell death in rats in vivo. The objective of this proposal is to investigate a series of hypotheses related to the pathological consequences of activation of the membrane attack complex in the cortex of mammalian brain. Parallel investigations will be performed in awake, freely moving rats in vivo and in organotypic explant cultures of rat hippocampus and in primary cultures of embryonic rat cortical cells in vitro.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS036808-05
Application #
6470177
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Jacobs, Margaret
Project Start
1998-04-01
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
5
Fiscal Year
2002
Total Cost
$365,750
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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McNamara, James O (2002) B cells and epilepsy: the odd couple. Neurology 58:677-8
Xiong, Zhi Qi; McNamara, James O (2002) Fleeting activation of ionotropic glutamate receptors sensitizes cortical neurons to complement attack. Neuron 36:363-74
Whitney, K D; McNamara, J O (2000) GluR3 autoantibodies destroy neural cells in a complement-dependent manner modulated by complement regulatory proteins. J Neurosci 20:7307-16
Yang, R; Puranam, R S; Butler, L S et al. (2000) Autoimmunity to munc-18 in Rasmussen's encephalitis. Neuron 28:375-83