title: Kynurenic acid modulates experimentally induced inflammation in the trigeminal ganglion.
abstract: BACKGROUND
  The trigeminal ganglion (TG) plays a central role in cranial pain. Administration of complete Freund's adjuvant (CFA) into the temporomandibular joint (TMJ) elicits activation of TG. Kynurenic acid (KYNA) is an endogenous excitatory amino acid receptor blocker, which may have an anti-inflammatory effect. We hypothesize that KYNA may reduce CFA-induced activation within the TG.
  
  
  METHODS
  A local inflammation was induced by administration of CFA into the TMJ in rats. KYNA and kynurenic acid amide 2 (KYNAA2) were intraperitoneally administered. We investigated changes of mitogen-activated protein kinases (MAPKs as ERK1/2, p38 and SAPK/JNK), NF-κB, CaMKII and DREAM, in addition to calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in the TG, with immunohistochemistry and Western blot at 2 and 10 days post-CFA injection.
  
  
  RESULTS
  We showed CFA-induces increases in pERK1/2, pp38, CaMKII, NF-κB and DREAM immunohistochemistry after 2 and 10 days. KYNAA2 displayed stronger effects on MAPKs than KYNA. Increased expression of CaMKII, NF-κB and DREAM were found in the neurons. Western blot showed significantly increase in pERK expression at 10 days post-CFA, which decreased after 10 days of KYNA treatment. Two days post-CFA, a significantly increase in pp38 expression was found, which decreased after 2 days of KYNA and KYNAA2 treatment.
  
  
  CONCLUSIONS
  The CFA-induced inflammatory model for the TG activation provided a time-related expression of MAPK (pERK1/2, pp38) and NF-κB. It involves both the neuronal and glial activation, which points to possible neuron-glia interactions during this process. The administration of the endogenous NMDA-receptor antagonists, KYNA and its derivative KYNAA2, resulted in the inhibition of the induced signaling system of the TG, which further points the importance of the glutamate receptors in this mechanism.
authors.affiliation: Department of Neurology, University of Szeged, Semmelweis 6, H-6725, Szeged, Hungary. csati.anett@med.u-szeged.hu.|Department of Medicine, Institute of Clinical Sciences, Lund University, Sölvegatan 17, SE 221 84, Lund, Sweden. csati.anett@med.u-szeged.hu.
authors.forename: A
authors.initials: A
authors.lastname: Csáti
authors.affiliation: Department of Medicine, Institute of Clinical Sciences, Lund University, Sölvegatan 17, SE 221 84, Lund, Sweden. lars.edvinsson@med.lu.se.
authors.forename: L
authors.initials: L
authors.lastname: Edvinsson
authors.affiliation: Department of Neurology, University of Szeged, Semmelweis 6, H-6725, Szeged, Hungary. vecsei.laszlo@med.u-szeged.hu.|MTA-SZTE Neuroscience Research Group, Szeged, Hungary. vecsei.laszlo@med.u-szeged.hu.
authors.forename: L
authors.initials: L
authors.lastname: Vécsei
authors.affiliation: MTA-SZTE Neuroscience Research Group, Szeged, Hungary. toldi@bio.u-szeged.hu.|Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary. toldi@bio.u-szeged.hu.
authors.forename: J
authors.initials: J
authors.lastname: Toldi
authors.affiliation: Institute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, Eotvos u. 6, 6720, Szeged, Hungary. fulop@pharm.u-szeged.hu.
authors.forename: F
authors.initials: F
authors.lastname: Fülöp
authors.affiliation: Department of Neurology, University of Szeged, Semmelweis 6, H-6725, Szeged, Hungary. tajti.janos@med.u-szeged.hu.|Department of Medicine, Institute of Clinical Sciences, Lund University, Sölvegatan 17, SE 221 84, Lund, Sweden. tajti.janos@med.u-szeged.hu.
authors.forename: J
authors.initials: J
authors.lastname: Tajti
authors.affiliation: Department of Medicine, Institute of Clinical Sciences, Lund University, Sölvegatan 17, SE 221 84, Lund, Sweden. karin.warfvinge@med.lu.se.
authors.forename: K
authors.identifier: http://orcid.org/0000-0002-1356-8725
authors.initials: K
authors.lastname: Warfvinge
mesh_terms: D000276:Adjuvants, Immunologic / Q000633:toxicity; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005620:Freund's Adjuvant / Q000633:toxicity; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D007736:Kynurenic Acid / Q000494:pharmacology*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D012668:Trigeminal Ganglion / Q000187:drug effects* / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D015415:Biomarkers; D015740:Calcitonin Gene-Related Peptide; D018691:Excitatory Amino Acid Antagonists; D005620:Freund's Adjuvant; D007736:Kynurenic Acid; D020929:Mitogen-Activated Protein Kinase Kinases; D019892:eIF-2 Kinase
keywords: Cell signaling pathways; Kynurenic acid; Kynurenic acid amide 2; Temporomandibular joint inflammation; Trigeminal ganglion