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

Annamária Fejes-Szabó, Zsuzsanna Bohár, E. Vámos, Gábor Nagy-Grócz, Lilla Tar, Gábor Veres, Dénes Zádori, Márton Szentirmai, J. Tajti, I. Szatmári, F. Fülöp, J. Toldi, A. Párdutz, L. Vécsei

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)725-738
Number of pages14
JournalJournal of Neural Transmission
Volume121
Issue number7
DOIs
Publication statusPublished - 2014

Fingerprint

Kynurenic Acid
Nitroglycerin
Amides
Nicotinic Receptors
Glutamic Acid
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Excitatory Amino Acid Antagonists
Nitric Oxide Synthase Type I
Calcitonin Gene-Related Peptide
Blood-Brain Barrier
Migraine Disorders
Sprague Dawley Rats
High Pressure Liquid Chromatography
Brain

Keywords

  • Cervical part of trigemino-cervical complex
  • Kynurenic acid
  • N-(2-N-pyrrolidinylethyl)-4-oxo- 1H-quinoline-2-carboxamide hydrochloride
  • Nitroglycerine
  • Trigeminal activation
  • Trigeminal sensitization

ASJC Scopus subject areas

  • Biological Psychiatry
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Medicine(all)

Cite this

Pre-treatment with new kynurenic acid amide dose-dependently prevents the nitroglycerine-induced neuronal activation and sensitization in cervical part of trigemino-cervical complex. / Fejes-Szabó, Annamária; Bohár, Zsuzsanna; Vámos, E.; Nagy-Grócz, Gábor; Tar, Lilla; Veres, Gábor; Zádori, Dénes; Szentirmai, Márton; Tajti, J.; Szatmári, I.; Fülöp, F.; Toldi, J.; Párdutz, A.; Vécsei, L.

In: Journal of Neural Transmission, Vol. 121, No. 7, 2014, p. 725-738.

Research output: Contribution to journalArticle

@article{f7efe94122614d6bb7f59a6652b1c76d,
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 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.",
keywords = "Cervical part of trigemino-cervical complex, Kynurenic acid, N-(2-N-pyrrolidinylethyl)-4-oxo- 1H-quinoline-2-carboxamide hydrochloride, Nitroglycerine, Trigeminal activation, Trigeminal sensitization",
author = "Annam{\'a}ria Fejes-Szab{\'o} and Zsuzsanna Boh{\'a}r and E. V{\'a}mos and G{\'a}bor Nagy-Gr{\'o}cz and Lilla Tar and G{\'a}bor Veres and D{\'e}nes Z{\'a}dori and M{\'a}rton Szentirmai and J. Tajti and I. Szatm{\'a}ri and F. F{\"u}l{\"o}p and J. Toldi and A. P{\'a}rdutz and L. V{\'e}csei",
year = "2014",
doi = "10.1007/s00702-013-1146-2",
language = "English",
volume = "121",
pages = "725--738",
journal = "Journal of Neural Transmission",
issn = "0300-9564",
publisher = "Springer Verlag",
number = "7",

}

TY - JOUR

T1 - Pre-treatment with new kynurenic acid amide dose-dependently prevents the nitroglycerine-induced neuronal activation and sensitization in cervical part of trigemino-cervical complex

AU - Fejes-Szabó, Annamária

AU - Bohár, Zsuzsanna

AU - Vámos, E.

AU - Nagy-Grócz, Gábor

AU - Tar, Lilla

AU - Veres, Gábor

AU - Zádori, Dénes

AU - Szentirmai, Márton

AU - Tajti, J.

AU - Szatmári, I.

AU - Fülöp, F.

AU - Toldi, J.

AU - Párdutz, A.

AU - Vécsei, L.

PY - 2014

Y1 - 2014

N2 - 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 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.

AB - 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 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.

KW - Cervical part of trigemino-cervical complex

KW - Kynurenic acid

KW - N-(2-N-pyrrolidinylethyl)-4-oxo- 1H-quinoline-2-carboxamide hydrochloride

KW - Nitroglycerine

KW - Trigeminal activation

KW - Trigeminal sensitization

UR - http://www.scopus.com/inward/record.url?scp=84903276838&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903276838&partnerID=8YFLogxK

U2 - 10.1007/s00702-013-1146-2

DO - 10.1007/s00702-013-1146-2

M3 - Article

C2 - 24385076

AN - SCOPUS:84903276838

VL - 121

SP - 725

EP - 738

JO - Journal of Neural Transmission

JF - Journal of Neural Transmission

SN - 0300-9564

IS - 7

ER -