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Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration
Author(s) -
Woodruff Trent M.,
Crane James W.,
Proctor Lavinia M.,
Buller Kathryn M.,
Shek Annie B.,
De Vos Kurt,
Pollitt Sandra,
Williams Hua M.,
Shiels Ian A.,
Monk Peter N.,
Taylor And Stephen M.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-5814com
Subject(s) - neurodegeneration , c5a receptor , neuroscience , pharmacology , receptor , medicine , chemistry , biology , immunology , disease , complement system , antibody
The complement system is thought to be involved in the pathogenesis of numerous neurological diseases, although its precise role remains controversial. In this study we used orally active C5a receptor antagonists (PMX53 and PMX205) developed in our laboratories in a rat model of 3‐nitropropionic acid (3‐NP) ‐induced Huntington's disease. Administration of the C5a antagonists (10 mg/kg/day, oral) either 48 h pre‐ or 48 h post‐toxin significantly reduced body weight loss, anorexia, and behavioral and motor deficits associated with 3‐NP intoxication. Striatal lesion size, apoptosis, neutrophil infiltration, and hemorrhage were also significantly reduced in C5a antagonist‐treated rats. Immunohistochemical analysis demonstrated marked deposition of C3 and C9, and upregulation of C5a receptors on neuronal cells at the time of lesion formation. Inhibition of prostaglandins or TNF‐α with ibuprofen or infliximab had no effect in this model. The C5a antagonists did not affect 3‐NP‐induced cell death when added directly to rat striatal neuronal cultures, indicating a secondary mechanism of action in vivo . Our findings demonstrate for the first time that complement activation in the brain, particularly C5a, is a key event in the pathogenesis of this disease model, and suggest a future role for inhibitors of C5a in the treatment of neurodegenerative diseases.—Woodruff, T. M., Crane, J. W., Proctor, L. M., Buller, K. M., Shek, A. B., de Vos, K., Pollitt, S., Williams, H. M., Shiels, I. A., Monk, P. N., Taylor, S. M. Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration. FASEB J. 20, 1407–1417 (2006)