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* School of Biomedical Sciences and
Queensland Brain Institute, University of Queensland, Brisbane, Australia;
Howard Florey Institute, University of Melbourne, Australia; and
Academic Neurology Unit and Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom
Complement activation products are elevated in the cerebrospinal fluid and spinal cord of patients with amyotrophic lateral sclerosis (ALS). In this study, we demonstrate complement system involvement in a rodent model of ALS (human SOD1G93A transgenic rats). With end-stage disease, SOD1G93A rats displayed marked deposition of C3/C3b, and a significant up-regulation of the C5aR in the lumbar spinal cord. This was associated with increased numbers of C5aR-positive astrocytes. However, expression of C5L2, the alternative receptor for C5a, was highest on motor neurons early in the disease process. To determine the contribution of C5a to the pathology displayed by this model of ALS, rats were administered an orally active, selective C5aR antagonist (PMX205; 1 mg/kg/day, oral). Animals treated with PMX205 displayed a significant extension of survival time and a reduction in end-stage motor scores, as compared with vehicle-treated rats. PMX205-treated animals also displayed reduced levels of astroglial proliferation in the lumbar spinal cord. This study provides the first demonstration of an involvement of C5a in an ALS model and suggests that inhibitors of complement activation could be beneficial in the treatment of this neurodegenerative disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants-in-Aid from the Motor Neuron Disease Research Institute of Australia (to T.M.W., P.G.N., and S.M.T.), a Project Grant from the National Health and Medical Research Council of Australia (Grant 455856 to S.M.T. and P.G.N.), and a Wellcome Trust project grant, UK (Grant 072231 to P.N.M.).
2 Address correspondence and reprint requests to Dr. Peter G. Noakes, School of Biomedical Sciences, University of Queensland, St. Lucia, Brisbane 4072, Australia. E-mail address: p.noakes{at}uq.edu.au
3 Abbreviations used in this paper: ALS, amyotrophic lateral sclerosis; C5L2, C5a-like receptor 2; GFAP, glial fibrillary acidic protein; ChAT, choline acetyltransferase; SOD1, copper–zinc superoxide dismutase; WT, wild type; ES, end stage; PS, presymptomatic.
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