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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.

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

Journal of neural transmission (Vienna, Austria : 1996) (2014-01-05)
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
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.

MATERIALS
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