{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:35:05Z","timestamp":1771335305955,"version":"3.50.1"},"reference-count":78,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001061","name":"Rebecca L. Cooper Medical Research Foundation","doi-asserted-by":"publisher","award":["PG2020710"],"award-info":[{"award-number":["PG2020710"]}],"id":[{"id":"10.13039\/501100001061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a strong neuroinflammatory component. Current treatments principally target the immune system but fail to preserve long\u2010term myelin health and do not prevent neurological decline. Studies over the past two decades have shown that the structurally related neuropeptides VIP and PACAP (vasoactive intestinal peptide and pituitary adenylate cyclase\u2010activating polypeptide, respectively) exhibit pronounced anti\u2010inflammatory activities and reduce clinical symptoms in MS disease models, largely via actions on their bivalent VIP receptor type 1 and 2. Here, using the cuprizone demyelination model, we demonstrate that PACAP and VIP, and strikingly the PACAP\u2010selective receptor PAC1 agonist maxadilan, prevented locomotor deficits in the horizontal ladder and open field tests. Moreover, only PACAP and maxadilan were able to prevent myelin deterioration, as assessed by a reduction in the expression of the myelin markers proteolipid protein 1, oligodendrocyte transcription factor 2, quaking\u20107 (APC) and Luxol Fast Blue staining. Furthermore, PACAP and maxadilan (but not VIP), prevented striatal synaptic loss and diminished astrocyte and microglial activation in the corpus callosum of cuprizone\u2010fed mice. In\u00a0vitro, PACAP or maxadilan prevented lipopolysaccharide (LPS)\u2010induced polarisation of primary astrocytes at 12\u201324\u2009h, an effect that was not seen with maxadilan in LPS\u2010stimulated microglia. Taken together, our data demonstrates for the first time that PAC1 agonists provide distinctive protective effects against white matter deterioration, neuroinflammation and consequent locomotor dysfunctions in the cuprizone model. The results indicate that targeting the PAC1 receptor may provide a path to treat myelin\u2010related diseases in humans.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16199-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.16199","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T10:21:07Z","timestamp":1723112467000},"page":"3250-3267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting the <scp>PAC1<\/scp> receptor mitigates degradation of myelin and synaptic markers and diminishes locomotor deficits in the cuprizone demyelination model"],"prefix":"10.1111","volume":"168","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0721-4055","authenticated-orcid":false,"given":"Margo I.","family":"Jansen","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science University of Technology Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasir","family":"Mahmood","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science University of Technology Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science University of Technology Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5444-0920","authenticated-orcid":false,"given":"Sarah Thomas","family":"Broome","sequence":"additional","affiliation":[{"name":"Semel Institute for Neuroscience and Human Behavior\/Neuropsychiatric Institute, Intellectual and Developmental Disabilities Research Center University of California, Los Angeles  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2727-9876","authenticated-orcid":false,"given":"James A.","family":"Waschek","sequence":"additional","affiliation":[{"name":"Semel Institute for Neuroscience and Human Behavior\/Neuropsychiatric Institute, Intellectual and Developmental Disabilities Research Center University of California, Los Angeles  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7037-759X","authenticated-orcid":false,"given":"Alessandro","family":"Castorina","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science University of Technology Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-016-0626-3"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1007622107"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161211795589364"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2007.09.084"},{"key":"e_1_2_10_6_1","first-page":"690","article-title":"Passage of pituitary adenylate cyclase activating polypeptide1\u201027 and pituitary adenylate cyclase activating polypeptide1\u201038 across the blood\u2010brain barrier","volume":"267","author":"Banks W. 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