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

IF 7.9 1区医学 Q1 CLINICAL NEUROLOGY

Journal of Headache and Pain Pub Date : 2025-08-05 DOI:10.1186/s10194-025-02127-8

Xuyan Jin, Andreia Morais, Yuichi Sasaki, Qingling Zhai, Pradeep Banerjee, Andrea Harriott, Cenk Ayata

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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.

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小分子CGRP拮抗剂不影响大鼠皮质扩张性抑制的易感性。

背景：Atogepant是一种小分子非竞争性降钙素基因相关肽（CGRP）受体拮抗剂，可有效预防阵发性偏头痛。皮层扩张性去极化（CSD）是偏头痛先兆下缓慢传播的去极化波。我们研究了同聚剂治疗偏头痛的疗效是否通过抑制CSD介导。方法：采用Sprague-Dawley大鼠（雄性28只，雌性28只），在异氟醚麻醉下，采用皮质内玻璃微电极，监测动脉血压、血气等全系统生理监测，测定连续外用1 M KCl诱导CSD的电刺激强度阈值和连续外用KCl诱导CSD的频率。在另一个单独的队列中，我们通过在对侧半球使用每天1 M KCl诱导3个CSD，连续2天破坏血脑屏障，然后进行CSD敏感性测试。两组患者均接受联合剂（30mg /kg，每日一次口服灌胃）或载药治疗，持续4天。最后一次给药后1 h检测CSD敏感性。结果：与载药相比，无论有无既往CSD，同效剂均不影响CSD阈值、频率、传播速度、振幅或持续时间。两组间系统生理参数无差异。结论：这些数据表明，即使血脑屏障通透性增加，抗偏头痛药物的疗效也不是通过抑制CSD来调节的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Headache and Pain 医学-临床神经学

CiteScore

11.80

自引率

13.50%

发文量

143

审稿时长

6-12 weeks

期刊介绍： The Journal of Headache and Pain, a peer-reviewed open-access journal published under the BMC brand, a part of Springer Nature, is dedicated to researchers engaged in all facets of headache and related pain syndromes. It encompasses epidemiology, public health, basic science, translational medicine, clinical trials, and real-world data. With a multidisciplinary approach, The Journal of Headache and Pain addresses headache medicine and related pain syndromes across all medical disciplines. It particularly encourages submissions in clinical, translational, and basic science fields, focusing on pain management, genetics, neurology, and internal medicine. The journal publishes research articles, reviews, letters to the Editor, as well as consensus articles and guidelines, aimed at promoting best practices in managing patients with headaches and related pain.