The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis.
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 SOD1(G93A) transgenic rats). With end-stage disease, SOD1(G93A) 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.
Woodruff
Trent M
TM
School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
Costantini
Kerina J
KJ
Crane
James W
JW
Atkin
Julie D
JD
Monk
Peter N
PN
Taylor
Stephen M
SM
Noakes
Peter G
PG
D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D003176:Complement C3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003179:Complement C3b / Q000096:biosynthesis; D015936:Complement C5a / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000627:therapeutic use; D051381:Rats; D055647:Rats, Transgenic; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D003176:Complement C3; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; C504156:hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl); D003179:Complement C3b; D015936:Complement C5a; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase