Small-molecule CGRP antagonist atogepant does not affect cortical spreading depression susceptibility in rats

Abstract

Background: Atogepant is a small-molecule non-competitive calcitonin gene-related peptide (CGRP) receptor antagonist efficacious in preventing episodic migraine. Cortical spreading depolarization (CSD) is a slowly propagating depolarization wave underlying migraine aura. We investigated whether the efficacy of atogepant in migraine is mediated by CSD suppression.

Method: We used Sprague-Dawley rats (n = 28 males, 28 females) to determine the electrical stimulation intensity threshold for CSD induction and the frequency of CSDs induced by continuous topical 1 M KCl application sequentially in the same animal, using intracortical glass microelectrodes under isoflurane anesthesia and full systemic physiological monitoring, including arterial blood pressure and blood gases. In a separate cohort, we disrupted the BBB by inducing three CSDs in the contralateral hemisphere using 1 M KCl daily for 2 days before CSD susceptibility testing. Both cohorts received atogepant (30 mg/kg, once daily oral gavage) or vehicle for four days. CSD susceptibility was examined 1 h after the last atogepant dose.

Results: Atogepant did not affect the CSD threshold, frequency, propagation speed, amplitude, or duration compared with vehicle, either without or with preceding CSDs. Systemic physiological parameters did not differ between groups.

Conclusions: These data suggest that atogepant efficacy in migraine is not mediated via CSD suppression, even when BBB permeability is increased.

Keywords: Atogepant; Blood-brain barrier; CGRP; Migraine; Spreading depression.

Fig. 1

CSD susceptibility following atogepant administration. A Experimental timeline. B Schematic illustration of burr hole placement and representative traces of CSD recordings. C The upper row shows the threshold, propagation speed, duration, and amplitude of CSDs induced by electrical stimulation in the right hemisphere. The lower row shows the topical 1 M KCl-induced CSD frequency, propagation speed, duration, and amplitude in the left hemisphere. CSD threshold, frequency, and propagation speed were analyzed using the Mann-Whitney test. CSD duration and amplitude were analyzed using two-way ANOVA

Fig. 2

CSD susceptibility following atogepant administration after BBB disruption. A Experimental timeline. B and C Schematic illustration of burr hole placement and representative traces of CBF and CSD recordings. D The upper row shows the threshold, propagation speed, duration, and amplitude of CSDs induced by electrical stimulation in the right hemisphere. The lower row shows the topical 1 M KCl-induced CSD frequency, propagation speed, duration, and amplitude in the right hemisphere. CSD threshold, frequency, and propagation speed were analyzed using the Mann-Whitney test. CSD duration and amplitude were analyzed using two-way ANOVA

Fig. 3

CSD-induced CBF responses following atogepant administration. A Experimental timeline. B Schematic illustration of burr hole placement and representative traces of CBF and CSD recordings. C Average CSD-induced CBF responses compared between the vehicle and atogepant groups in both hemispheres. CBF was analyzed using two-way ANOVA