A novel kynurenic acid analogue: a comparison with kynurenic acid. An in vitro electrophysiological study

Marosi, Máté; Nagy, Dávid; Farkas, Tamás; Kis, Zsolt; Rózsa, Éva; Robotka, Hermina; Fülöp, Ferenc; Vécsei, László; Toldi, József

doi:10.1007/s00702-009-0346-2

Cited by 41 publications

(31 citation statements)

References 18 publications

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“…Currently, 4-chlorokynurenine is a phase I compound with an active Investigational New Drug application on file at the FDA for neuropathic pain and in the event of a positive result, it is hoped to be developed for other indications such as epilepsy, Huntington's disease and PD (http://www.vistagen.com/). Systemic application of a new KYNA analog, 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride causes central effects that are comparable to those of KYNA [69]. Although this needs to be verified experimentally, these effects suggest that the analog, unlike KYNA itself, crosses the BBB [69,70].…”

Section: Therapeutic Approaches For Modulation Of the Kynurenine Pathmentioning

confidence: 83%

Altered tryptophan metabolism in Parkinson's disease: A possible novel therapeutic approach

Szabó

Kincses

Toldi

et al. 2011

Journal of the Neurological Sciences

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Section: Therapeutic Approaches For Modulation Of the Kynurenine Pathmentioning

confidence: 83%

Altered tryptophan metabolism in Parkinson's disease: A possible novel therapeutic approach

Szabó

Kincses

Toldi

et al. 2011

Journal of the Neurological Sciences

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“…Following this comparative study, KA-1 was tested in several experimental setups and proved to have beneficial effects (Gellért et al, 2012Knyihar-Csillik et al, 2008;Marosi et al, 2010;Vámos et al, 2010Vámos et al, , 2009Zádori et al, 2011c). 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).…”

Section: Introductionmentioning

confidence: 99%

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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“…1 The structures of kynurenic acid (KynA) and of the new KYNA analogue 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride (Marosi et al 2010) volunteers by Ficoll-Hypaque (Sigma Chemicals) density gradient centrifugation. Cells were washed with PBS and resuspended in 80 μl of buffer consisting of PBS with 0.5% of bovine serum albumin and 2 mM EDTA per 10 7 total cells and 20 μl of magnetic MACS anti-CD14 MicroBeads (Miltenyi Biotec, Germany) per total 10 7 total cells and incubated for 15 min at 6-8°C.…”

Section: Isolation and Stimulation Of Human Monocytesmentioning

confidence: 99%

“…Conventionally, α defensins are involved in microbial killing, but they also have an important immunomodulative role in inflammation . We further compared the effects of KynA with those of a novel, synthetic KynA analogue 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride, which is able to cross the blood-brain barrier (Marosi et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Different inhibitory effects of kynurenic acid and a novel kynurenic acid analogue on tumour necrosis factor-α (TNF-α) production by mononuclear cells, HMGB1 production by monocytes and HNP1-3 secretion by neutrophils

Tiszlavicz

Németh

Fülöp

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Kynurenic acid (KynA), a broad spectrum antagonist of excitatory amino acid receptors, may serve as a protective agent in neurological disorders. The potential anti-inflammatory effect of KynA in human leukocytes has not been characterized. The aim of this study was to compare the effects of KynA with those of a new analogue, 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride on tumour necrosis factor-α (TNF-α) production and high mobility group box protein 1 (HMGB1) secretion. The effects of KynA on granulocyte activation were investigated via the secretion of human neutrophil peptide 1-3 (HNP1-3). Peripheral blood mononuclear cells and granulocytes or CD14 positive monocytes were applied as effector cells, or whole blood cultures were used. TNF-α, HMGB1 and HNP1-3 concentrations were determined by ELISA, TNF-α and HNP1-3 mRNA expressions were quantified by reverse transcription PCR. KynA attenuated the TNF-α production of human mononuclear cells activated by heat-inactivated Staphylococcus aureus, inhibiting TNF-α production at the transcription level. Furthermore, KynA diminished HMGB1 secretion by U 937 monocytic cells and by peripheral blood monocytes. KynA inhibited the HNP1-3 secretion in whole blood and in granulocyte cultures. The suppressive effect of the KynA analogue was more potent than that of an equimolar concentration KynA in TNF-α, HMGB1 and HNP1-3 inhibition. These results suggest that the new KynA analogue has a more potent immunoregulatory effect than KynA on human mononuclear cells, monocytes and granulocytes and indicate the potential benefits of further exploration of its uses in human inflammatory disease.

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A novel kynurenic acid analogue: a comparison with kynurenic acid. An in vitro electrophysiological study

Cited by 41 publications

References 18 publications

Altered tryptophan metabolism in Parkinson's disease: A possible novel therapeutic approach

Altered tryptophan metabolism in Parkinson's disease: A possible novel therapeutic approach

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

Different inhibitory effects of kynurenic acid and a novel kynurenic acid analogue on tumour necrosis factor-α (TNF-α) production by mononuclear cells, HMGB1 production by monocytes and HNP1-3 secretion by neutrophils

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