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: Gábor Veres, Annamária Fejes-Szabó, Dénes Zádori, Gábor Nagy-Grócz, Anna M László, Attila Bajtai, István Mándity, Márton Szentirmai, Zsuzsanna Bohár, Klaudia Laborc, István Szatmári, Ferenc Fülöp, László Vécsei, Árpád Párdutz
• Journal: Journal of neural transmission (Vienna, Austria : 1996) (J Neural Transm (Vienna)) Vol. 124 Issue 1 Pg. 99-112 (01 2017) ISSN: 1435-1463 [Electronic] Austria
• PMID: 27629500 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Proto-Oncogene Proteins c-fos
• Formaldehyde
• Kynurenic Acid

Topics

• Analgesics (blood, pharmacokinetics, pharmacology)
• Animals
• Chromatography, High Pressure Liquid
• Disease Models, Animal
• Facial Pain (drug therapy, pathology, physiopathology)
• Formaldehyde
• Immunohistochemistry
• Kynurenic Acid (analogs & derivatives, blood, pharmacokinetics, pharmacology)
• Male
• Motor Activity (drug effects)
• Neurons (drug effects, metabolism, pathology)
• Proto-Oncogene Proteins c-fos (metabolism)
• Rats, Sprague-Dawley
• Trigeminal Nuclei (drug effects, metabolism, pathology)
• Vibrissae