Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration
| Autor: | Lavinia M. Proctor, Kurt J. De Vos, Kathryn M. Buller, Trent M. Woodruff, Peter N. Monk, Annie B. Shek, Ian A. Shiels, Stephen M. Taylor, Hua M. Williams, Sandra Pollitt, James W. Crane |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Neurotoxins Central nervous system Ibuprofen Inflammation Pharmacology Biology Peptides Cyclic Biochemistry C5a receptor Pathogenesis 03 medical and health sciences 0302 clinical medicine Genetics medicine Animals Receptor Receptor Anaphylatoxin C5a Molecular Biology Cells Cultured Neurons Neurodegeneration Nitro Compounds medicine.disease Rats 3. Good health Complement system Disease Models Animal Huntington Disease medicine.anatomical_structure Mechanism of action Rats Inbred Lew Immunology Receptors Chemokine Propionates medicine.symptom 030217 neurology & neurosurgery 030215 immunology Biotechnology |
| Zdroj: | The FASEB Journal. 20:1407-1417 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.05-5814com |
| Popis: | 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 up-regulation 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. |
| Databáze: | OpenAIRE |
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