Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration.
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.
Woodruff
Trent M
TM
Promics Ltd., The University of Queensland, Brisbane, QLD 4072, Australia. trent.woodruff@promics.com
Crane
James W
JW
Proctor
Lavinia M
LM
Buller
Kathryn M
KM
Shek
Annie B
AB
de Vos
Kurt
K
Pollitt
Sandra
S
Williams
Hua M
HM
Shiels
Ian A
IA
Monk
Peter N
PN
Taylor
Stephen M
SM
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology*; D007052:Ibuprofen / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D009574:Nitro Compounds / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D019707:Receptors, Chemokine
C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); C417003:C5aR2 protein, human; D009498:Neurotoxins; D009574:Nitro Compounds; D010456:Peptides, Cyclic; D011422:Propionates; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; C015392:3-nitropropionic acid; D007052:Ibuprofen