Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration

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. and Taylor, Stephen M. (2006) Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration. FASEB Journal, 20 9: 1407-1417. doi:10.1096/fj.05-5814com

Author 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, Stephen M.
Title Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration
Journal name FASEB Journal   Check publisher's open access policy
ISSN 0892-6638
Publication date 2006-07-01
Sub-type Article (original research)
DOI 10.1096/fj.05-5814com
Volume 20
Issue 9
Start page 1407
End page 1417
Total pages 11
Place of publication Bethesda, MD, U.S.A.
Publisher Federation of American Societies for Experimental Biology
Language eng
Subject C1
730104 Nervous system and disorders
06 Biological Sciences
Formatted abstract
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-alpha 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.
Keyword Biochemistry & Molecular Biology
Cell Biology
Complement System
3-nitropropionic Acid
Toxin 3-nitropropionic Acid
Anaphylatoxin C5a
Striatal Lesions
Human Leukocytes
Q-Index Code C1

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Created: Wed, 15 Aug 2007, 17:59:37 EST