Journal Article Epublish
PubMed: 42650796 DOI: 10.3390/biom16081128
Pharmacological Modulation of the Kynurenine Pathway Using PF-04859989 Modulates PACAP Signaling in Migraine-Relevant Trigeminal Sensitization.
Biomolecules 16(8)
Authors: Evelin Vágvölgyi-Sümegi, Gábor Nagy-Grócz, Zsolt Galla, Edina Katalin Cseh, Zoltán István Tapody, Péter Monostori, János Tajti, Péter Klivényi, László Vécsei, Tamás Körtési
Affiliations
- Department of Theoretical Health Sciences and Health Management, Faculty of Health Sciences and Social Studies, University of Szeged, Temesvári krt. 31, H-6726 Szeged, Hungary.
- HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, Danube Neuroscience Research Laboratory, University of Szeged, Tisza Lajos krt. 113, H-6725 Szeged, Hungary.
- 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.
- Metabolic and Newborn Screening Laboratory, Department of Pediatrics, University of Szeged, Korányi Fasor 14-15, H-6720 Szeged, Hungary.
- Department of Neurology, Albert Szent-Györgyi Faculty of Medicine and Clinical Center, University of Szeged, H-6725 Szeged, Hungary.
- Department of Theoretical Health Sciences and Health Management, Faculty of Health Sciences and Social Studies, University of Szeged, Temesvári krt. 31, H-6726 Szeged, Hungary. Department of Neurology, Albert Szent-Györgyi Faculty of Medicine and Clinical Center, University of Szeged, H-6725 Szeged, Hungary.
Abstract
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's 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-PACAP interactions and may identify novel migraine-related therapeutic targets.
MeSH
Pituitary Adenylate Cyclase-Activating Polypeptide, Kynurenine, Migraine Disorders, Neuropeptides, Therapeutics, Kynurenic Acid