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

Abstract

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.

AMPA receptor GluA1 Ser831 phosphorylation is critical for nitroglycerin-induced migraine-like pain

“…Previous studies demonstrate that NTG administration causes a delayed migraine-like pain in migraineurs and an immediate headache in both migraine sufferers and healthy subjects (Ashina et al, 2013; Olesen, 2008; Thomsen et al, 1994). Because NTG-produced nitric oxide can modulate cortical spreading depression in humans and rodents (Petzold et al, 2008) and NTG can also enhance the propagation of cortical spreading depression (Knapp et al, 2017), the NTG-induced migraine model might display the cortical spreading depression-mediated aura. The administration of NTG not only triggers migraine in humans, but also produces cutaneous hyperalgesia in rodents (Ramachandran et al, 2012; Tassorelli et al, 2003).…”

Systematic review of the pharmacological agents that have been tested against spreading depolarizations

“…Ketamine, a proven blocker of SD, has been shown to stop the neurological aura symptoms in some patients but had no effect on the headache. 120 Many migraine drugs from different pharmacological classes have been tested against SD so far, 50,97,102,110,179,185,[192][193][194][195][196][197][198][199][200][201][202][203][204][205][206][207] and topiramate and flunarizine were most effective since they exerted an inhibitory effect in all of the revised studies.…”

“…A dose-dependent reduction of the numbers and amplitude and a deceleration of KCl-induced SDs in isolated chicken retinas at a dosage from 0.05 to 2.00 mM 205,228 was observed in the late 1990s, while more recently published studies support these observations. 110,204 However, the scientific status of this agent is ambivalent, and some studies observed no reductive effect on SD. 194,203,229 Additional anti-migraine drugs that were effective against SDs are lamotrigine, 185 riboflavin, 185 methylsergide, 50,205 amitryptoline, 50 and propranolol, 50,205,206 but only a few experiments exist.…”

Interactions between the Kynurenine and the Endocannabinoid System with Special Emphasis on Migraine

“…Cortical spreading depression (CSD) is a self propagating wave in the cortical areas of the brain and it has a relevant role in the pathomechanism of migraine [ 52 ], as it is well accepted that CSD is the basis of the aura phenomena [ 53 ]. In the model of CSD, two new KYNA analogs inhibited the propagation of CSD waves [ 54 ], likely by the inhibition of glutamate receptors. Since glutamate receptors have a crucial role in the propagation and generation of CSD [ 55 ], they possibly represent a link between migraine and CSD.…”