{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T08:47:28Z","timestamp":1785746848454,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"HUN-REN-SZTE Neuroscience Research Group","award":["2000607"],"award-info":[{"award-number":["2000607"]}]},{"DOI":"10.13039\/501100015763","name":"University of Szeged Open Access Fund","doi-asserted-by":"publisher","award":["8811"],"award-info":[{"award-number":["8811"]}],"id":[{"id":"10.13039\/501100015763","id-type":"DOI","asserted-by":"publisher"}]},{"award":["8811"],"award-info":[{"award-number":["8811"]}],"id":[{"id":"https:\/\/ror.org\/01pnej532","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Migraine is a disabling neurological disorder in which neuropeptides, particularly pituitary adenylate cyclase-activating polypeptide (PACAP), play pathogenic roles. The kynurenine pathway (KP) is increasingly implicated in migraine-related glutamatergic and neuroinflammatory mechanisms. Previously, we showed that the neuroprotective metabolite kynurenic acid attenuates PACAP overexpression following trigeminovascular activation. This study investigated the effects of kynurenine aminotransferase II (KAT-II) inhibition on PACAP expression and KP metabolites during trigeminal sensitization. Methods: Rats received Complete Freund\u2019s Adjuvant (CFA) or saline injection into the right whisker pad. KAT-II inhibitor PF-04859989 (16 and 32 mg\/kg) or saline was administered intraperitoneally 72 h later. Blood samples and nucleus trigeminus caudalis (TNC) were collected for PACAP and KP quantification. Results: CFA treatment induced significant PACAP overexpression in the TNC and altered peripheral KP metabolite levels. PF-04859989 further increased PACAP expression, reaching significance at the 16 mg\/kg dose, whereas no significant additional effect was observed at 32 mg\/kg. In parallel, treatment with PF-04859989 altered peripheral KP metabolite concentrations in the peripheral inflammatory model, predominantly at the lower dose. Conclusions: This study demonstrates that KAT-II inhibition by PF-04859989 modulates PACAP signaling and KP metabolism under trigeminal inflammatory conditions. These findings support KP\u2013PACAP interactions and may identify novel migraine-related therapeutic targets.<\/jats:p>","DOI":"10.3390\/biom16081128","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T08:04:59Z","timestamp":1785744299000},"page":"1128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological Modulation of the Kynurenine Pathway Using PF-04859989 Modulates PACAP Signaling in Migraine-Relevant Trigeminal Sensitization"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5808-5600","authenticated-orcid":false,"given":"Evelin","family":"V\u00e1gv\u00f6lgyi-S\u00fcmegi","sequence":"first","affiliation":[{"name":"Department of Theoretical Health Sciences and Health Management, Faculty of Health Sciences and Social Studies, University of Szeged, Temesv\u00e1ri krt. 31, H-6726 Szeged, Hungary"},{"name":"HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, Danube Neuroscience Research Laboratory, University of Szeged, Tisza Lajos krt. 113, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2121-4625","authenticated-orcid":false,"given":"G\u00e1bor","family":"Nagy-Gr\u00f3cz","sequence":"additional","affiliation":[{"name":"Department of Theoretical Health Sciences and Health Management, Faculty of Health Sciences and Social Studies, University of Szeged, Temesv\u00e1ri krt. 31, H-6726 Szeged, Hungary"},{"name":"Preventive Health Sciences Research Group, Incubation Competence Centre of the Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Galla","sequence":"additional","affiliation":[{"name":"Metabolic and Newborn Screening Laboratory, Department of Pediatrics, University of Szeged, Kor\u00e1nyi Fasor 14-15, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edina Katalin","family":"Cseh","sequence":"additional","affiliation":[{"name":"Department of Neurology, Albert Szent-Gy\u00f6rgyi Faculty of Medicine and Clinical Center, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1239-0600","authenticated-orcid":false,"given":"Zolt\u00e1n Istv\u00e1n","family":"Tapody","sequence":"additional","affiliation":[{"name":"Department of Theoretical Health Sciences and Health Management, Faculty of Health Sciences and Social Studies, University of Szeged, Temesv\u00e1ri krt. 31, H-6726 Szeged, Hungary"},{"name":"Department of Neurology, Albert Szent-Gy\u00f6rgyi Faculty of Medicine and Clinical Center, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3591-6054","authenticated-orcid":false,"given":"P\u00e9ter","family":"Monostori","sequence":"additional","affiliation":[{"name":"Metabolic and Newborn Screening Laboratory, Department of Pediatrics, University of Szeged, Kor\u00e1nyi Fasor 14-15, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e1nos","family":"Tajti","sequence":"additional","affiliation":[{"name":"Department of Neurology, Albert Szent-Gy\u00f6rgyi Faculty of Medicine and Clinical Center, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5389-3266","authenticated-orcid":false,"given":"P\u00e9ter","family":"Kliv\u00e9nyi","sequence":"additional","affiliation":[{"name":"HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, Danube Neuroscience Research Laboratory, University of Szeged, Tisza Lajos krt. 113, H-6725 Szeged, Hungary"},{"name":"Department of Neurology, Albert Szent-Gy\u00f6rgyi Faculty of Medicine and Clinical Center, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"V\u00e9csei","sequence":"additional","affiliation":[{"name":"HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, Danube Neuroscience Research Laboratory, University of Szeged, Tisza Lajos krt. 113, H-6725 Szeged, Hungary"},{"name":"Department of Neurology, Albert Szent-Gy\u00f6rgyi Faculty of Medicine and Clinical Center, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam\u00e1s","family":"K\u00f6rt\u00e9si","sequence":"additional","affiliation":[{"name":"Department of Theoretical Health Sciences and Health Management, Faculty of Health Sciences and Social Studies, University of Szeged, Temesv\u00e1ri krt. 31, H-6726 Szeged, Hungary"},{"name":"HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, Danube Neuroscience Research Laboratory, University of Szeged, Tisza Lajos krt. 113, H-6725 Szeged, Hungary"},{"name":"Preventive Health Sciences Research Group, Incubation Competence Centre of the Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"03331024261418704","DOI":"10.1177\/03331024261418704","article-title":"Migraine as a Primary Care-Sensitive Condition: Building Pathways to Accessible Care","volume":"46","author":"Oliveira","year":"2026","journal-title":"Cephalalgia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s10194-026-02291-5","article-title":"Meningeal Neuropeptide 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