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01.07.2014 | Neurology and Preclinical Neurological Studies - Original Article

Pre-treatment with new kynurenic acid amide dose-dependently prevents the nitroglycerine-induced neuronal activation and sensitization in cervical part of trigemino-cervical complex

verfasst von: Annamária Fejes-Szabó, Zsuzsanna Bohár, Enikő Vámos, Gábor Nagy-Grócz, Lilla Tar, Gábor Veres, Dénes Zádori, Márton Szentirmai, János Tajti, István Szatmári, Ferenc Fülöp, József Toldi, Árpád Párdutz, László Vécsei

Erschienen in: Journal of Neural Transmission | Ausgabe 7/2014

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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 (KYNA_a) 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 KYNA_a 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. KYNA_a 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. KYNA_a also mitigated the behavioural changes after nitroglycerine. Thus, in this model KYNA_a 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.

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Titel: Pre-treatment with new kynurenic acid amide dose-dependently prevents the nitroglycerine-induced neuronal activation and sensitization in cervical part of trigemino-cervical complex
verfasst von: Annamária Fejes-Szabó
Zsuzsanna Bohár
Enikő Vámos
Gábor Nagy-Grócz
Lilla Tar
Gábor Veres
Dénes Zádori
Márton Szentirmai
János Tajti
István Szatmári
Ferenc Fülöp
József Toldi
Árpád Párdutz
László Vécsei
Publikationsdatum: 01.07.2014
Verlag: Springer Vienna
Erschienen in: Journal of Neural Transmission / Ausgabe 7/2014
Print ISSN: 0300-9564
Elektronische ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-013-1146-2

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Pre-treatment with new kynurenic acid amide dose-dependently prevents the nitroglycerine-induced neuronal activation and sensitization in cervical part of trigemino-cervical complex

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