title: A comparative assessment of two kynurenic acid analogs in the formalin model of trigeminal activation: a behavioral, immunohistochemical and pharmacokinetic study.
abstract: Kynurenic acid (KYNA) has well-established protective properties against glutamatergic neurotransmission, which plays an essential role in the activation and sensitization process during some primary headache disorders. The goal of this study was to compare the effects of two KYNA analogs, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-1) and N-(2-N-pyrrolidinylethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-2), in the orofacial formalin test of trigeminal pain. Following pretreatment with KA-1 or KA-2, rats were injected with subcutaneous formalin solution in the right whisker pad. Thereafter, the rubbing activity and c-Fos immunoreactivity changes in the spinal trigeminal nucleus pars caudalis (TNC) were investigated. To obtain pharmacokinetic data, KA-1, KA-2 and KYNA concentrations were measured following KA-1 or KA-2 injection. Behavioral tests demonstrated that KA-2 induced larger amelioration of formalin-evoked alterations as compared with KA-1 and the assessment of c-Fos immunoreactivity in the TNC yielded similar results. Although KA-1 treatment resulted in approximately four times larger area under the curve values in the serum relative to KA-2, the latter resulted in a higher KYNA elevation than in the case of KA-1. With regard to TNC, the concentration of KA-1 was under the limit of detection, while that of KA-2 was quite small and there was no major difference in the approximately tenfold KYNA elevations. These findings indicate that the differences between the beneficial effects of KA-1 and KA-2 may be explained by the markedly higher peripheral KYNA levels following KA-2 pretreatment. Targeting the peripheral component of trigeminal pain processing would provide an option for drug design which might prove beneficial in headache conditions.
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.|MTA-SZTE Neuroscience Research Group, Szeged, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Veres
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.
authors.forename: Annamária
authors.initials: A
authors.lastname: Fejes-Szabó
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.
authors.forename: Dénes
authors.initials: D
authors.lastname: Zádori
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.|Faculty of Health Sciences and Social Studies, University of Szeged, Szeged, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Nagy-Grócz
authors.affiliation: Department of Biometrics and Agricultural Informatics, Faculty of Horticultural Science, Szent Istvan University, Budapest, Hungary.
authors.forename: Anna M
authors.initials: AM
authors.lastname: László
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Bajtai
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Mándity
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.
authors.forename: Márton
authors.initials: M
authors.lastname: Szentirmai
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.|MTA-SZTE Neuroscience Research Group, Szeged, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bohár
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Laborc
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Szatmári
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary. vecsei.laszlo@med.u-szeged.hu.|MTA-SZTE Neuroscience Research Group, Szeged, Hungary. vecsei.laszlo@med.u-szeged.hu.
authors.forename: László
authors.initials: L
authors.lastname: Vécsei
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.
authors.forename: Árpád
authors.initials: Á
authors.lastname: Párdutz
mesh_terms: D000700:Analgesics / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005157:Facial Pain / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005557:Formaldehyde; D007150:Immunohistochemistry; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D014278:Trigeminal Nuclei / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014738:Vibrissae
chemical_list: D000700:Analgesics; D016760:Proto-Oncogene Proteins c-fos; D005557:Formaldehyde; D007736:Kynurenic Acid
keywords: Formalin test; Kynurenic acid analog; Pharmacokinetics; Rat; Trigeminal pain