A comparative assessment of two kynurenic acid analogs in the formalin model of trigeminal activation: a behavioral, immunohistochemical and pharmacokinetic study

Abstract

Abstract:Kynurenic acid (KYNA) has well-established protective properties against glutamatergic neurotransmission, which plays an essential role in the activation and sensitization process during headache disorders. The goal of this study was to Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporationcompare 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 a 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 10-fold 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. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationReviewer #2: The Authors have tried to address the comments of the referees and partially improved the manuscript. Some issues still need improvement.The sentence 'glutamatergic neurotransmission, which plays an essential role in the activation and sensitization process during headache disorders' is incorrect. This statement may be true for some primary headaches (migraine and chronic migraine), but not for 'headaches' in general.The sentence was modified accordingly.The way the data are presented is still quite confusing:Description of the time boundaries for Phase I and II is missing in the Methods section. The Methods section was supplemented with the requested information.A Figure ( Table 1 reports the levels of significance for data presented in Figure 2: the table should be inglobated in said figure otherwise the reader is forced to go back and forth.The requested modification was done in Figure 2 and Table 1 was removed. Table 2 should be associated to a figure that illustrates mean+sd of time spent in rubbing during the 2 phases of formalin in the di...

Neurotransmitter and tryptophan metabolite concentration changes in the complete Freund’s adjuvant model of orofacial pain

“…Furthermore, some of the developed analogs also displayed promising results in different animal models of headache [31,[82][83][84][85]. In an earlier study we investigated two KYNA analogs where both of them proved to be effective in the formalin model of trigeminal pain [84]. However, one of them was more effective than the other and according to our analyses the better performing compound caused a more pronounced elevation of KYNA concentration on the periphery, whereas in the CNS the concentrations of KYNA were similar.…”

“…Accordingly, the antinociceptive properties of KYNA were proved in animal models of pain [29,81]. Furthermore, some of the developed analogs also displayed promising results in different animal models of headache [31,[82][83][84][85]. In an earlier study we investigated two KYNA analogs where both of them proved to be effective in the formalin model of trigeminal pain [84].…”

Neurotransmitter and tryptophan metabolite concentration changes in the Complete Freund’s adjuvant model of orofacial pain

“…Furthermore, some of the developed analogs also displayed promising results in different animal models of headache [31,[82][83][84][85]. In an earlier study we investigated two KYNA analogs where both of them proved to be effective in the formalin model of trigeminal pain [84].…”

Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects

“…The spectrum of action that occurs following the treatment with different KYNA analogues is still untangled. Ongoing behavioral, immunohistochemical and pharmacokinetic studies might elucidate the possible effect site of the KYNA analogues [145]. A possible interaction between KYNA and inflammatory cytokines (IFNα, IFNγ, TNFα, TGF-β, IL-1β, IL4, IL6, IL23) suggests an interaction between the kynurenine pathway and the immune system, leading to the idea that one possible site of action for KYNA derivates could be neurogenic inflammation [146,147].…”