The kynurenate analog SZR-72 prevents the nitroglycerol-induced increase of c-fos immunoreactivity in the rat caudal trigeminal nucleus: Comparative studies of the effects of SZR-72 and kynurenic acid

Knyihár‐Csillik, Elizabeth; Mihály, András; Krisztin-Péva, Beáta; Robotka, Hermina; Szatmári, István; Fülöp, Ferenc; Toldi, József; Csillik, B.; Vécsei, László

doi:10.1016/j.neures.2008.04.009

Cited by 64 publications

(45 citation statements)

References 18 publications

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“…c-Fos expression level sensitively correlates with neuronal activity after physiological stimuli or in pathological states (Kaczmarek, 2002). Kynurenergic manipulation proved to attenuate the pathological elevation of c-Fos protein expression in different experimental models (Knyihar-Csillik et al, 2008). The direct intraplantar administration of KYNA or the systemic administration of its precursor L-KYNs, can effectively reduce the chemically-induced c-Fos expression level in various pain models (Zhang et al, 2003; Knyihár-Csillik et al, 2007a,b).…”

Section: Discussionmentioning

confidence: 99%

Systemic L-Kynurenine sulfate administration disrupts object recognition memory, alters open field behavior and decreases c-Fos immunopositivity in C57Bl/6 mice

Varga

Herédi

Kánvási

et al. 2015

Front. Behav. Neurosci.

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L-Kynurenine (L-KYN) is a central metabolite of tryptophan degradation through the kynurenine pathway (KP). The systemic administration of L-KYN sulfate (L-KYNs) leads to a rapid elevation of the neuroactive KP metabolite kynurenic acid (KYNA). An elevated level of KYNA may have multiple effects on the synaptic transmission, resulting in complex behavioral changes, such as hypoactivity or spatial working memory deficits. These results emerged from studies that focused on rats, after low-dose L-KYNs treatment. However, in several studies neuroprotection was achieved through the administration of high-dose L-KYNs. In the present study, our aim was to investigate whether the systemic administration of a high dose of L-KYNs (300 mg/bwkg; i.p.) would produce alterations in behavioral tasks (open field or object recognition) in C57Bl/6j mice. To evaluate the changes in neuronal activity after L-KYNs treatment, in a separate group of animals we estimated c-Fos expression levels in the corresponding subcortical brain areas. The L-KYNs treatment did not affect the general ambulatory activity of C57Bl/6j mice, whereas it altered their moving patterns, elevating the movement velocity and resting time. Additionally, it seemed to increase anxiety-like behavior, as peripheral zone preference of the open field arena emerged and the rearing activity was attenuated. The treatment also completely abolished the formation of object recognition memory and resulted in decreases in the number of c-Fos-immunopositive-cells in the dorsal part of the striatum and in the CA1 pyramidal cell layer of the hippocampus. We conclude that a single exposure to L-KYNs leads to behavioral disturbances, which might be related to the altered basal c-Fos protein expression in C57Bl/6j mice.

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Section: Discussionmentioning

confidence: 99%

Systemic L-Kynurenine sulfate administration disrupts object recognition memory, alters open field behavior and decreases c-Fos immunopositivity in C57Bl/6 mice

Varga

Herédi

Kánvási

et al. 2015

Front. Behav. Neurosci.

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“…The beneficial effects of KYNA46 and its different analogues have been proven in different migraine models. The KYNA analogue SZR-72 mitigated systemic NTG-induced increase in the number of neurons expressing c-Fos47 and nNOS 48. Furthermore, SZR-72 attenuated the NTG-induced decrease of histochemical changes in the caudal trigeminal nucleus 49.…”

Section: Discussionmentioning

confidence: 96%

Nitroglycerin enhances the propagation of cortical spreading depression: comparative studies with sumatriptan and novel kynurenic acid analogues

Knapp¹,

Szita²,

Kocsis³

et al. 2016

DDDT

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BackgroundThe complex pathophysiology of migraine is not yet clearly understood; therefore, experimental models are essential for the investigation of the processes related to migraine headache, which include cortical spreading depression (CSD) and NO donor-induced neurovascular changes. Data on the assessment of drug efficacy in these models are often limited, which prompted us to investigate a novel combined migraine model in which an effective pharmacon could be more easily identified.Materials and methodsIn vivo electrophysiological experiments were performed to investigate the effect of nitroglycerin (NTG) on CSD induced by KCl application. In addition, sumatriptan and newly synthesized neuroactive substances (analogues of the neuromodulator kynurenic acid [KYNA]) were also tested.ResultsThe basic parameters of CSDs were unchanged following NTG administration; however, propagation failure was decreased compared to the controls. Sumatriptan decreased the number of CSDs, whereas propagation failure was as minimal as in the NTG group. On the other hand, both of the KYNA analogues restored the ratio of propagation to the control level.DiscussionThe ratio of propagation appeared to be the indicator of the effect of NTG. This is the first study providing direct evidence that NTG influences CSD; furthermore, we observed different effects of sumatriptan and KYNA analogues. Sumatriptan changed the generation of CSDs, whereas the analogues acted on the propagation of the waves. Our experimental design overlaps with a large spectrum of processes present in migraine pathophysiology, and it can be a useful experimental model for drug screening.

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“…Activity induced by electrical stimulation of the trigeminal ganglion, resulting in increased c-fos immunoreactivity in the caudal trigeminal nucleus, was almost abolished by kynurenate infusion in rats [45]. Kynurenate was shown to inhibit the delayed trigeminal activation induced by glyceroltrinitrate, using CamKII or cFos as a marker [46,47]. Combined inhibition of AMPA and kainate receptors was effective as treatment for migraine [48].…”

Section: Discussionmentioning

confidence: 99%

Release of CGRP from mouse brainstem slices indicates central inhibitory effect of triptans and kynurenate

et al. 2014

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BackgroundCGRP is contained in a substantial proportion of unmyelinated trigeminal neurons innervating intracranial tissues. Previously, we have described a hemisected rodent scull preparation and later the intact trigeminal ganglion to measure stimulated CGRP release from trigeminal afferents.MethodsHere, we establish a preparation for examining CGRP release from central trigeminal terminals using single fresh slices of the mouse medullary brainstem.ResultsBasal and stimulated amount of CGRP substantially exceeded the detection level. Experiments were designed as matched pairs of at least six brainstem slices per animal. Stimulation with high potassium induced calcium-dependent and reversible CGRP release. Capsaicin stimulation of TRPV1 provoked concentration-dependent CGRP release. The anti-migraine drug naratriptan did not inhibit capsaicin-induced CGRP release from peripheral terminals but inhibited the release from brainstem slices. The glutamate antagonist kynurenate showed a similar pattern of site-specific inhibition of CGRP release.ConclusionsAs observed earlier for other drugs used in the treatment of migraine this indicates that the central terminals in the spinal trigeminal nucleus may be the main site of action. The preparation allows evaluating the trigeminal brainstem as a pharmacological site of action.

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The kynurenate analog SZR-72 prevents the nitroglycerol-induced increase of c-fos immunoreactivity in the rat caudal trigeminal nucleus: Comparative studies of the effects of SZR-72 and kynurenic acid

Cited by 64 publications

References 18 publications

Systemic L-Kynurenine sulfate administration disrupts object recognition memory, alters open field behavior and decreases c-Fos immunopositivity in C57Bl/6 mice

Systemic L-Kynurenine sulfate administration disrupts object recognition memory, alters open field behavior and decreases c-Fos immunopositivity in C57Bl/6 mice

Nitroglycerin enhances the propagation of cortical spreading depression: comparative studies with sumatriptan and novel kynurenic acid analogues

Release of CGRP from mouse brainstem slices indicates central inhibitory effect of triptans and kynurenate

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