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

Abstract

Background: 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.

Results: 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.

Discussion: 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.

Keywords: cortical spreading depression; kynurenic acid analogues; migraine; nitroglycerin; sumatriptan.

Figure 1

Experimental design and representative recording from the 2-hour period following KCl administration. Notes: On the left, filled circles indicate the exposed skull areas (1, −2, and −5 mm from the bregma in the anterior–posterior axis, respectively; 2 mm from the bregma in the medial–lateral axis). KCl (1 M) was applied at the posterior hole. Direct-current electrodes E₁ and E₂ were positioned at a distance of 3 mm from each other. The silver electrocorticography electrode was placed next to the E₁ electrode. Vertical bars 10 mV (direct current) and 500 μV. Horizontal bar 10 minutes.

Figure 2

Experimental design of the different groups. Numbers represent hours of recording. Abbreviations: NTG, nitroglycerin; CSD, cortical spreading depression; Suma, sumatriptan.

Figure 3

CSD frequency and ratio of propagation. Notes: (A) Number of CSDs/2 hours in all experiments and groups. The connecting lines show the data from single experiments, recorded by E₁ and E₂. The slope of the lines indicates the ratio of propagation, based on the different CSD number recorded by the two electrodes. In this parameter, significant differences were observed in the control group and both of the NTG + SZR groups (pairwise comparison within the groups with Friedman’s ANOVA; *P=0.046, 0.046, 0.025). (B) Average (±SD) CSD numbers in the different groups, detected by E₁ and E₂. Significant decrease in CSD number recorded by E₂ was observed in the NTG + Suma group using multiple comparison between the groups and electrodes (Kruskal–Wallis ANOVA; ⁺P=0.032). Horizontal lines within bars represents CSD number (mean ± SD) in the first hour. There was no significant difference between the first and second hour recorded by either of the electrodes in any groups. (C) Average (±SD) ratio of propagation in the different groups (CSDs at E₂/CSDs at E₁). Abbreviations: CSD, cortical spreading depression; NTG, nitroglycerin; ANOVA, analysis of variance; SD, standard deviation; Suma, sumatriptan.