Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
Ann Neurol. 2020 Oct;88(4):771-784. doi: 10.1002/ana.25831. Epub 2020 Aug 7.
Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia.
Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro.
Olcegepant (1mg/kg, single dose) increased infarct risk after 12- to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21, p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle, p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold, p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta.
Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition. ANN NEUROL 2020;88:771-784.
降钙素基因相关肽（CGRP）通路抑制剂是治疗偏头痛的新兴疗法。然而，CGRP 介导的血管舒张是缺血的关键抢救机制。因此，我们研究了小分子 CGRP 受体拮抗剂 gepants 是否会加重脑缺血。
在小鼠中，大脑中动脉闭塞 12 至 60 分钟。我们比较了奥来替康（单次或每日 10 次 0.1-1mg/kg）或利美替康（单次 10-100mg/kg）预处理与载体相比，梗死风险和体积、侧支血流和神经功能缺损。我们还在体外确定了它们对 CGRP 诱导的小鼠和人血管舒张的作用。
奥来替康（1mg/kg，单次剂量）增加了模拟短暂性缺血发作的 12 至 20 分钟闭塞后的梗死风险（14/19 与载体相比，6/18，相对风险=2.21，p<0.022），并使 60 分钟闭塞后的梗死体积加倍（p<0.001），并加重神经功能缺损（中位数评分=9 与载体相比，5，p=0.008）。每日 0.1 至 1mg/kg 奥来替康 10 次也得出了类似的结果。利美替康 10mg/kg 使 20 分钟缺血后的梗死体积增加 60%（p=0.03）；60 分钟闭塞后 100mg/kg 导致 75%的死亡率。在家族性偏瘫性偏头痛 1 型小鼠中，奥来替康 1mg/kg 使 30 分钟闭塞后的梗死体积增加了 1.6 倍（p=0.017）。两种 gepants 均一致降低侧支血流并减少再灌注成功。奥来替康对 CGRP 诱导的小鼠主动脉舒张的作用比利美替康强 10 倍。
Gepants 通过侧支功能障碍加重了小鼠的缺血性中风。因此，CGRP 通路阻滞剂可能会加重偶然发生的脑缺血事件。因此，这些药物的脑血管安全性必须更好地确定，特别是在有缺血事件风险增加或预防性 CGRP 抑制的患者中。
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