{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:33:04Z","timestamp":1791462784402,"version":"4.3.4"},"reference-count":33,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2017,3,3]],"date-time":"2017-03-03T00:00:00Z","timestamp":1488499200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008714","name":"Motor Neurone Disease Research Institute of Australia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008714","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1082271"],"award-info":[{"award-number":["APP1082271"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2017,4]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. The complement system is up\u2010regulated in ALS, with recent studies indicating that the activation product C5a accelerates disease progression via the C5a<jats:sub>1<\/jats:sub> receptor (C5aR1). We therefore examined the therapeutic effect of C5a<jats:sub>1<\/jats:sub> receptor antagonism in hSOD1<jats:sup>G93A<\/jats:sup> mice, the most widely used preclinical model of ALS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The selective and orally active C5a<jats:sub>1<\/jats:sub> receptor antagonist, PMX205, was administered to hSOD1<jats:sup>G93A<\/jats:sup> mice in drinking water, both pre\u2010 and post\u2010disease onset. Blood, brain and spinal cord pharmacokinetics were performed using LC\u2013MS\/MS methods. Effects of PMX205 on hSOD1<jats:sup>G93A<\/jats:sup> disease progression was determined using body weight, hindlimb grip strength, survival time and blood analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>PMX205 entered the intact CNS at pharmacologically active concentrations, with increased entry observed in hSOD1<jats:sup>G93A<\/jats:sup> mice as the disease progressed, in line with augmented blood\u2013brain barrier breakdown. hSOD1<jats:sup>G93A<\/jats:sup> mice 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\u2010inflammatory monocytes and granulocytes and increases in T\u2010helper lymphocytes in peripheral blood. PMX205 treatment beginning 3\u00a0weeks following disease onset also attenuated disease progression, significantly extending survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>These results confirm that C5a<jats:sub>1<\/jats:sub> receptors play a pathogenic role in hSOD1<jats:sup>G93A<\/jats:sup> mice, further validating the C5a\u2010C5a<jats:sub>1<\/jats:sub> receptor signalling axis as a potential therapeutic target to slow disease progression in ALS.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13730","type":"journal-article","created":{"date-parts":[[2017,1,27]],"date-time":"2017-01-27T11:17:22Z","timestamp":1485515842000},"page":"689-699","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":105,"title":["Pharmacological inhibition of complement C5a\u2010C5a<sub>1<\/sub> receptor signalling ameliorates disease pathology in the hSOD1<sup>G93A<\/sup> mouse model of amyotrophic lateral sclerosis"],"prefix":"10.1111","volume":"174","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9976-7396","authenticated-orcid":false,"given":"John D","family":"Lee","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences The University of Queensland  Brisbane Qld Australia"},{"name":"University of Queensland Centre for Clinical Research The University of Queensland  Brisbane Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod","family":"Kumar","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The University of Queensland  Brisbane Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny N T","family":"Fung","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The University of Queensland  Brisbane Qld Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc 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