Department of Clinical Experimental Research, Glostrup Research Institute, Copenhagen University Hospital, Glostrup, Denmark.
Department of Clinical Experimental Research, Glostrup Research Institute, Copenhagen University Hospital, Glostrup, Denmark; Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden.
Eur J Pharmacol. 2019 Dec 1;864:172726. doi: 10.1016/j.ejphar.2019.172726. Epub 2019 Oct 4.
CGRP plays a major role in the pathophysiology of migraine. Concomitant, CGRP plays a role in endogenous neurovascular protection from severe vasoconstriction associated with e.g. cerebral or cardiac ischemia. The CGRP antagonistic antibodies Fremanezumab (TEVA Pharmaceuticals) and Erenumab (Novartis/Amgen) have successfully been developed for the prevention of frequent migraine attacks. Whereas these antibodies might challenge endogenous neurovasular protection during severe cerebral or coronary vasoconstriction, potential future therapeutic CGRP agonists might induce migraine-like headaches in migraineurs. In the current study segments of cerebral artery have been used to obtain mechanistic insight of the CGRP-neutralizing anti-body Fremanezumab in neurovascular regulation in vitro. The basilar artery was selected due to its relevance in subarachnoid hemorrhage (SAH). Erenumab is known to block the human CGRP receptor and Fremanezumab to neutralize both human and rat CGRP. Results confirmed that Erenumab does not block the rat CGRP receptor and that Fremanezumab inhibits the vasodilatory effect induced by both human CGRP, rat CGRP and the metabolically stable CGRP analog, SAX in rat basilar artery. Fremanezumab also inhibits the vasodilatory effect of capsaicin in constricted segments of basilar artery. Capsaicin is used as a pharmacological tool to induce secretion of endogenous perivascular CGRP and our studies confirm that the antibody reach the perivascular sensory synaptic cleft and blocks the vasodilatory response of released CGRP in the present in vitro model. Thus, CGRP neutralization might have the mechanistic potential to block vasoprotective responses to severe vasoconstriction provided they reach the site of action and Fremanezumab is an important tool for future investigations of the impact of CGRP physiology.
降钙素基因相关肽（CGRP）在偏头痛的病理生理学中起主要作用。同时，CGRP 在防止与例如脑或心脏缺血相关的严重血管收缩引起的内源性神经血管保护中发挥作用。CGRP 拮抗剂抗体 Fremanezumab（TEVA 制药公司）和 Erenumab（诺华/安进）已成功开发用于预防频繁偏头痛发作。虽然这些抗体可能会在严重的脑或冠状动脉收缩期间挑战内源性神经血管保护，但潜在的未来治疗性 CGRP 激动剂可能会在偏头痛患者中引起偏头痛样头痛。在目前的研究中，使用脑动脉段在体外神经血管调节中获得了 CGRP 中和抗体 Fremanezumab 的机制见解。选择基底动脉是因为它与蛛网膜下腔出血（SAH）有关。已知 Erenumab 阻断人 CGRP 受体，Fremanezumab 中和人 CGRP 和大鼠 CGRP。结果证实 Erenumab 不阻断大鼠 CGRP 受体，Fremanezumab 抑制人 CGRP、大鼠 CGRP 和代谢稳定的 CGRP 类似物 SAX 在大鼠基底动脉中诱导的血管舒张作用。Fremanezumab 还抑制辣椒素在基底动脉收缩段诱导的血管舒张作用。辣椒素用作诱导内源性血管周围 CGRP 分泌的药理学工具，我们的研究证实该抗体到达血管周围感觉突触裂，并在目前的体外模型中阻断释放的 CGRP 的血管舒张反应。因此，CGRP 中和可能具有阻止严重血管收缩的血管保护反应的机制潜力，前提是它们到达作用部位并且 Fremanezumab 是未来研究 CGRP 生理学影响的重要工具。
