{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:29:11Z","timestamp":1783470551597,"version":"3.55.0"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,8,17]],"date-time":"2025-08-17T00:00:00Z","timestamp":1755388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["process #88887.501568\/2020-00"],"award-info":[{"award-number":["process #88887.501568\/2020-00"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["process #88887.897008\/2023-00"],"award-info":[{"award-number":["process #88887.897008\/2023-00"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["process #401653\/2022-6"],"award-info":[{"award-number":["process #401653\/2022-6"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["process #303531\/2020-7"],"award-info":[{"award-number":["process #303531\/2020-7"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004263","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio Grande do Sul","doi-asserted-by":"publisher","award":["process #21\/2551-0001935-2"],"award-info":[{"award-number":["process #21\/2551-0001935-2"]}],"id":[{"id":"10.13039\/501100004263","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004263","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio Grande do Sul","doi-asserted-by":"publisher","award":["process# 401653\/2022-6"],"award-info":[{"award-number":["process# 401653\/2022-6"]}],"id":[{"id":"10.13039\/501100004263","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Relapsing-remitting multiple sclerosis (RRMS) is characterized by increased oxidative compound production and neuroinflammation, accompanied by neuropathic pain and anxiety. Activation of nicotinamide adenine dinucleotide phosphate oxidase (Nox) generates oxidative stress by-products that induce nociception and anxiety-like behaviours by transient receptor potential ankyrin 1 (TRPA1) activation in the relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) model. Nox activation stimulates myeloperoxidase (MPO), producing advanced oxidation protein products (AOPPs). AOPPs are oxidative stress biomarkers and agonists of the receptor for advanced glycation end products (RAGE). Elevated plasma AOPP levels in multiple sclerosis are associated with disability progression, suggesting that the AOPPs\/MPO\/Nox pathway contributes to TRPA1 activation. This study investigated AOPP-mediated TRPA1 activation in a RR-EAE mouse model using pharmacological interventions and TRPA1 gene deletion.<\/jats:p>\n                  <jats:p>We tested AOPP-induced intracellular calcium influx in HEK cells transfected with TRPA1 and in dorsal root ganglion (DRG) neurons isolated from wild-type (Trpa1+\/+) and TRPA1-deficient (Trpa1\u2212\/\u2212) mice. In vivo, Trpa1+\/+ and Trpa1\u2212\/\u2212 female C57BL\/6J mice received intrathecal (i.t.) AOPPs (0.1\u201330\u2005nmol\/site) with or without the TRPA1 antagonists (HC030031 and A967079, 10\u2005nmol\/site i.t.), or the RAGE antagonist (FPS-ZM1, 10\u2005nmol\/site, i.t.). In the RR-EAE model, we assessed the effect of non-specific Nox inhibition on the AOPPs pathway activity using apocynin (APO; 100\u2005mg\/kg, intragastric) administered for 15 days, evaluating nociception and anxiety-like behaviour. Following APO treatment, we measured AOPP levels, MPO\/Nox activity, neuroinflammatory biomarkers and demyelination in the spinal cord and brain. We evaluated the effects of anti-AOPP antibody (5\u2005\u00b5l\/site, i.t.) in blocking RR-EAE- and AOPP-induced nociception and anxiety-like behaviour to selectively inhibit AOPP action.<\/jats:p>\n                  <jats:p>AOPPs selectively induced calcium influx in TRPA1-transfected HEK cells and DRG neurons from Trpa1+\/+ mice. AOPP administration triggered nociception, which was blocked by TRPA1 antagonists but not by the RAGE antagonist. Trpa1+\/+ mice showed AOPP-induced nociception and phosphorylated extracellular signal-regulated kinase (p-Erk) signalling in the spinal cord dorsal horn, while Trpa1\u2212\/\u2212 mice exhibited no nociceptive behaviour or p-Erk signalling. APO treatment reduced AOPP levels, MPO\/Nox activation, nociception, anxiety-like behaviour, neuroinflammation, spinal cord and brain demyelination in the RR-EAE model. Acute anti-AOPP injections exerted antinociceptive and anxiolytic-like effects in RR-EAE- and AOPP-induced nociception by lowering spinal cord and brain AOPP levels.<\/jats:p>\n                  <jats:p>Our findings highlight AOPPs as a TRPA1 agonist and as contributors to nociception, anxiety-like behaviour and neuroinflammation in RR-EAE, suggesting that targeting AOPPs may offer a novel approach for managing these symptoms. Therefore, targeting the AOPP formation pathway may provide a novel therapeutic strategy for RRMS patients.<\/jats:p>","DOI":"10.1093\/brain\/awaf306","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T11:56:22Z","timestamp":1755172582000},"page":"1332-1348","source":"Crossref","is-referenced-by-count":2,"title":["Advanced oxidation protein products activated TRPA1 in a neuropathic multiple sclerosis model"],"prefix":"10.1093","volume":"149","author":[{"given":"Patr\u00edcia","family":"Rodrigues","sequence":"first","affiliation":[{"name":"Graduate Program in Pharmacology, Federal University of Santa Maria (UFSM) , Santa Maria, RS 97105-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia Maria","family":"Frare","sequence":"additional","affiliation":[{"name":"Graduate Program in Biological Sciences, Federal University of Santa Maria (UFSM) , Santa Maria, RS 97105-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00e1thaly Andrighetto","family":"Ruviaro","sequence":"additional","affiliation":[{"name":"Graduate Program in Biological Sciences, Federal University of Santa Maria (UFSM) , Santa Maria, RS 97105-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diulle Spat","family":"Peres","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmacology, Federal University of Santa Maria (UFSM) , Santa Maria, RS 97105-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda Tibolla","family":"Viero","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmacology, Federal University of Santa Maria (UFSM) , Santa Maria, RS 97105-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Iuri Felix","family":"Moraes","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmacology, Federal University of Santa Maria (UFSM) , Santa Maria, RS 97105-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caren","family":"Antoniazzi","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmacology, Federal University of Santa Maria (UFSM) , Santa Maria, RS 97105-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"dos Santos Stein","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmaceutical Sciences, Federal University of Santa Maria (UFSM) , Santa Maria, RS 97105-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Clara","family":"Machado","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmacology, Federal University of Santa Maria (UFSM) , Santa Maria, RS 97105-900 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Padilha","family":"Dalenogare","sequence":"additional","affiliation":[{"name":"Graduate Program in Pharmacology, Federal University of Santa Maria (UFSM) , Santa Maria, RS 97105-900 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"De Logu","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Oncology Section, Department of Health Sciences, University of Florence , Florence 50139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierangelo","family":"Geppetti","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Oncology Section, Department of Health Sciences, University of Florence , Florence 50139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Nassini","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Oncology Section, Department of Health Sciences, University of Florence , 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