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


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          The 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 methods

          In 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.


          The 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.


          The 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.

          Most cited references45

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          Kynurenines in the CNS: recent advances and new questions.

          Various pathologies of the central nervous system (CNS) are accompanied by alterations in tryptophan metabolism. The main metabolic route of tryptophan degradation is the kynurenine pathway; its metabolites are responsible for a broad spectrum of effects, including the endogenous regulation of neuronal excitability and the initiation of immune tolerance. This Review highlights the involvement of the kynurenine system in the pathology of neurodegenerative disorders, pain syndromes and autoimmune diseases through a detailed discussion of its potential implications in Huntington's disease, migraine and multiple sclerosis. The most effective preclinical drug candidates are discussed and attention is paid to currently under-investigated roles of the kynurenine pathway in the CNS, where modulation of kynurenine metabolism might be of therapeutic value.
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            Suppression of cortical spreading depression in migraine prophylaxis.

            Topiramate, valproate, propranolol, amitriptyline, and methysergide have been widely prescribed for migraine prophylaxis, but their mechanism or site of action is uncertain. Cortical spreading depression (CSD) has been implicated in migraine and as a headache trigger and can be evoked in experimental animals by electrical or chemical stimulation. We hypothesized that migraine prophylactic agents suppress CSD as a common mechanism of action. Rats were treated either acutely or chronically over weeks and months, with one of the above migraine prophylactic drugs, vehicle, or D-propranolol, a clinically ineffective drug. The impact of treatment was determined on the frequency of evoked CSDs after topical potassium application or on the incremental cathodal stimulation threshold to evoke CSD. Chronic daily administration of migraine prophylactic drugs dose-dependently suppressed CSD frequency by 40 to 80% and increased the cathodal stimulation threshold, whereas acute treatment was ineffective. Longer treatment durations produced stronger CSD suppression. Chronic D-propranolol treatment did not differ from saline control. Our data suggest that CSD provides a common therapeutic target for widely prescribed migraine prophylactic drugs. Assessing CSD threshold may prove useful for developing new prophylactic drugs and improving upon existing ones.
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              Cortical spreading depression triggers migraine attack: pro.

              Cenk Ayata (2010)
              More than 60 years ago Aristides Leão coined the term spreading depression (SD) to describe a transient "depression" of electrocorticographic activity that lasts up to several minutes and slowly "spreads" in all directions in cortex by way of gray matter contiguity.(1) Today we know that SD is an intrinsic electrophysiological property of central nervous systems, evolutionarily preserved from locust to man.(2-7) Largely based on the similarities between the symptomatology of migraine aura and the electrophysiological features of SD, a causal relationship between the two has long been hypothesized.(8-10) Recently, the SD theory of migraine gained momentum by evidence emerging from both clinical and experimental studies despite being challenged by alternative mechanisms and hypotheses. Here, I will review the accumulated evidence supporting a causal relationship between SD and migraine aura and headache, and discuss the contested notion that SD may also be involved in migraine attacks without a "perceived" aura.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                20 December 2016
                : 11
                : 27-34
                [1 ]Department of Physiology, Anatomy, and Neuroscience, University of Szeged
                [2 ]MTA-SZTE Neuroscience Research Group
                [3 ]Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary
                Author notes
                Correspondence: József Toldi, Department of Physiology, Anatomy, and Neuroscience, University of Szeged, 52 Közép Fasor, Szeged 6726, Hungary, Tel +36 62 544 149, Fax +36 62 544 291, Email toldi@ 123456bio.u-szeged.hu
                © 2017 Knapp et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                migraine,cortical spreading depression,nitroglycerin,sumatriptan,kynurenic acid analogues


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