title: Pharmacological inhibition of complement C5a-C5a1receptor signalling ameliorates disease pathology in the hSOD1G93Amouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. The complement system is up-regulated in ALS, with recent studies indicating that the activation product C5a accelerates disease progression via the C5a1receptor (C5aR1). We therefore examined the therapeutic effect of C5a1receptor antagonism in hSOD1G93Amice, the most widely used preclinical model of ALS.
  
  
  
  The selective and orally active C5a1receptor antagonist, PMX205, was administered to hSOD1G93Amice in drinking water, both pre- and post-disease onset. Blood, brain and spinal cord pharmacokinetics were performed using LC-MS/MS methods. Effects of PMX205 on hSOD1G93Adisease progression was determined using body weight, hindlimb grip strength, survival time and blood analysis.
  
  
  
  PMX205 entered the intact CNS at pharmacologically active concentrations, with increased entry observed in hSOD1G93Amice as the disease progressed, in line with augmented blood-brain barrier breakdown. hSOD1G93Amice treated with PMX205 before disease onset had significantly improved hindlimb grip strength, slower disease progression and extended survival, compared with vehicle treatment. These improvements were associated with reductions in pro-inflammatory monocytes and granulocytes and increases in T-helper lymphocytes in peripheral blood. PMX205 treatment beginning 3 weeks following disease onset also attenuated disease progression, significantly extending survival.
  
  
  
  These results confirm that C5a1receptors play a pathogenic role in hSOD1G93Amice, further validating the C5a-C5a1receptor signalling axis as a potential therapeutic target to slow disease progression in ALS.
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Qld, Australia.|University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: John D
authors.identifier: 0000-0002-9976-7396
authors.initials: JD
authors.lastname: Lee
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Jenny N T
authors.initials: JN
authors.lastname: Fung
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Qld, Australia.|Queensland Brain Institute, The University of Queensland, Brisbane, Qld, Australia.|Trauma, Critical Care and Recovery, Brisbane Diamantina Health Partners, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Ruitenberg
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Qld, Australia.|Queensland Brain Institute, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Noakes
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072105:Superoxide Dismutase-1 / Q000378:metabolism*
chemical_list: D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; C000606290:SOD1 protein, human; C504156:hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl); D000072105:Superoxide Dismutase-1