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, Enikő; Nagy-Grócz, Gábor; Tar, Lilla; Veres, Gábor; Zádori, Dénes; Szentirmai, Márton; Tajti, János; Szatmári, István; Fülöp, Ferenc; Toldi, József; Párdutz, Árpád; Vécsei, László

doi:10.1007/s00702-013-1146-2

Cited by 29 publications

(33 citation statements)

References 63 publications

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“…KYNA-A1 was able to mitigate nNOS, CamKIIα and CGRP immunoreactivity changes after NTG administration, and KYNA-A2 had the same, but dose dependent effect [136,143,144]. These results clearly demonstrate the important role of L-KYN and KYNA in trigeminal nociceptive processing, and support their important role in migraine pathomechanism.…”

Section: Kynurenines In Migrainesupporting

confidence: 67%

Tryptophan Catabolites and Migraine

Bohár

Párdutz

Vécsei

2016

CPD

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Abstract:Migraine is a highly disabling neurological condition affecting around 15% of the population worldwide.Decades of intensive research shed some light on diseases pathomechanism, but information is still missing about the initiation of the attack. In the past century, serotonin emerged as the main target of both basic and therapeutic research. As a result, the triptans, the only approved migraine specific drugs were developed. The involvement of glutamatergic mechanism in migraine headache development such as cortical hyperexcitability, and cortical spreading depression as the pathological correlate of migraine aura called the attention to the kynurenine pathway in migraine pathomechanism. The serotonin and kynurenine pathways are closely connected, as they both are the metabolic routes of the amino acid tryptophan. Kynurenine catabolites are important participants in glutamatergic neurotransmission, regulation also nociceptive processing of the trigeminal system. The current work attempts to collect recent data on both serotonin and kynurenine research related to migraine and emphasizes the importance of further research on this topic.

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Section: Kynurenines In Migrainesupporting

confidence: 67%

Tryptophan Catabolites and Migraine

Bohár

Párdutz

Vécsei

2016

CPD

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“…region (Fejes-Szabó et al, 2014). To date there has been only one study of the pharmacokinetic properties of KYNA amides, which found that only a small proportion of KA-1 decays into KYNA in the serum of C57B/6 mice (Zádori et al, 2011a).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast with the electrophysiological findings with KA-1, N-(2-N-pyrrolidinylethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-2, Figure 1b) did not decrease, but rather slightly increased the amplitudes of field excitatory postsynaptic potentials (fEPSPs) (Nagy et al, 2011). However, in a recent study, pretreatment with KA-2 was also able to attenuate the effects of nitroglycerine (NTG) in an experimental model of migraine (Fejes-Szabó et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…The KYNA concentrations of the CNS samples were quantified on the basis of a slight modification of a literature method (Hervé et al, 1996) as described in detail with method validation in our previous article (Fejes-Szabó et al, 2014). For the measurement of concentration of the above-mentioned metabolite from serum samples we applied the same method with a slight modification.…”

Section: Chromatographic Conditionsmentioning

confidence: 99%

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

et al. 2016

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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...

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“…The photomicrographs of the stained sections of C1-C2 were taken using Zeiss After image acquisition, the laminae I-II in dorsal horn were defined manually as area of interest and a threshold grey level was validated with the image analysis software, as described in an earlier study (32,3536). The program calculated the area innervated by the immunoreactive fibres and cells as the number of pixels with densities above the threshold, the data were expressed as area fractions (%) of the corresponding immunolabelled structures.…”

Section: Immunohistochemistry (Trpv1 Nnos Nf-κb)mentioning

confidence: 99%

The modulatory effect of anandamide on nitroglycerin-induced sensitization in the trigeminal system of the rat

et al. 2016

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Background One of the human and animal models of migraine is the systemic administration of the nitric oxide donor (NO) nitroglycerin (NTG). NO can provoke migraine-like attacks in migraineurs and initiates a self-amplifying process in the trigeminal system, probably leading to central sensitization. Recent studies suggest that the endocannabinoid system is involved in nociceptive signal processing and cannabinoid receptor (CB) agonists are able to attenuate nociception in animal models of pain. Aim The purpose of the present study was to investigate the modulatory effects of a CB agonist anandamide (AEA) on the NTG-induced expression of transient receptor potential vanilloid type 1 (TRPV1), neuronal nitric oxide synthase (nNOS), nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2) and kynurenine aminotransferase-II (KAT-II) in the upper cervical spinal cord (C1–C2) of the rat, where most of the trigeminal nociceptive afferents convey. Methods A half hour before and one hour after NTG (10 mg/kg) or placebo injection, adult male Sprague-Dawley rats ( n = 44) were treated with AEA (2 × 5 mg/kg). Four hours after placebo/NTG injection, the animals were perfused and the cervical spinal cords were removed for immunohistochemistry and Western blotting. Results and conclusion Our results show that NTG is able to increase TRPV1, nNOS, NF-κB and COX-2 and decrease KAT-II expression in the C1–C2 segments. On the other hand, we have found that AEA modulates the NTG-induced changes, thus it influences the activation and central sensitization process in the trigeminal system, probably via CBs.

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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

Cited by 29 publications

References 63 publications

Tryptophan Catabolites and Migraine

Tryptophan Catabolites and Migraine

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

The modulatory effect of anandamide on nitroglycerin-induced sensitization in the trigeminal system of the rat

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