title: Pre-treatment with new kynurenic acid amide dose-dependently prevents the nitroglycerine-induced neuronal activation and sensitization in cervical part of trigemino-cervical complex.
abstract: The systemic administration of nitroglycerine induces attacks in migraineurs and is able to activate and sensitize the trigeminal system in animals involving glutamate and α7-nicotinic acetylcholine receptors, among others. Kynurenic acid is one of the endogenous glutamate receptor antagonists, and exerts inhibitory action on the α7-nicotinic acetylcholine receptors. Since kynurenic acid penetrates the blood-brain barrier poorly, therefore a newly synthesized kynurenic acid amide, N-(2-N-pyrrolidinylethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KYNAa) was used with such a side-chain substitution to facilitate brain penetration in our study. We evaluated its modulatory effect on kynurenic acid concentration in the cervical part of trigemino-cervical complex (C1-C2) and in the model of nitroglycerine-induced trigeminal activation using male Sprague-Dawley rats. One hour after 1 mmol/kg bodyweight KYNAa administration, the kynurenic acid level increased significantly in C1-C2, which returned to the basal level at 300 min measured by high-performance liquid chromatography. KYNAa pre-treatment had dose-dependent, mitigating action on nitroglycerine-induced decrease in calcitonin gene-related peptide and increase in c-Fos, neuronal nitric oxide synthase and calmodulin-dependent protein kinase II alpha expression in the C1-C2. KYNAa also mitigated the behavioural changes after nitroglycerine. Thus, in this model KYNAa is able to modulate in a dose-dependent manner the changes in neurochemical markers of activation and sensitization of the trigeminal system directly and indirectly--via forming kynurenic acid, possibly acting on peripheral and central glutamate or α7-nicotinic acetylcholine receptors. These results suggest that application of kynurenic acid derivatives could be a useful therapeutic strategy in migraine headache in the future with a different mechanism of action.
authors.affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.
authors.forename: Annamária
authors.initials: A
authors.lastname: Fejes-Szabó
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bohár
authors.forename: Enikő
authors.initials: E
authors.lastname: Vámos
authors.forename: Gábor
authors.initials: G
authors.lastname: Nagy-Grócz
authors.forename: Lilla
authors.initials: L
authors.lastname: Tar
authors.forename: Gábor
authors.initials: G
authors.lastname: Veres
authors.forename: Dénes
authors.initials: D
authors.lastname: Zádori
authors.forename: Márton
authors.initials: M
authors.lastname: Szentirmai
authors.forename: János
authors.initials: J
authors.lastname: Tajti
authors.forename: István
authors.initials: I
authors.lastname: Szatmári
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.forename: József
authors.initials: J
authors.lastname: Toldi
authors.forename: Árpád
authors.initials: Á
authors.lastname: Párdutz
authors.forename: László
authors.initials: L
authors.lastname: Vécsei
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D005106:Exploratory Behavior / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014278:Trigeminal Nuclei / Q000166:cytology* / Q000187:drug effects
chemical_list: C548511:2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride; D018691:Excitatory Amino Acid Antagonists; D006146:Guanidines; D016760:Proto-Oncogene Proteins c-fos; D052248:Nitric Oxide Synthase Type I; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D007736:Kynurenic Acid; D015740:Calcitonin Gene-Related Peptide; C056179:nitroguanidine