Safety of Anti-CGRP Migraine Therapeutics in Ischemic Stroke

小分子降钙素基因相关肽受体拮抗剂(Gepants)和抗CGRP或抗CGRP 降钙素基因相关肽受体单抗(Nezumabs)是治疗偏头痛的新方法。然而，内生性 降钙素基因相关肽是最有效的血管扩张分子之一，而降钙素基因相关肽介导的血管扩张是关键的救命稻草。 脑缺血的机制。因此，降钙素基因相关肽拮抗剂可能会增加脑血管事件的风险。 偏头痛。尽管存在这种明显的担忧，但偏头痛领域未得到满足的需求的规模推动了 尽管有血管并发症的病例报道，降钙素基因相关肽拮抗剂的临床进展。 我们最近报道，葛根素可加重大脑中动脉短暂闭塞(MCAO)后的预后。 在小鼠中模拟短暂性脑缺血发作(Mulder等人Ann Neurol，2020)。Gepant ARM明显更多 与对照组相比，更有可能发展为脑梗塞。随着MCAO时间的延长，脑梗塞体积，神经功能障碍和 咬人的手臂的死亡率也更高。大脑中动脉阻塞期间更严重的脑血流(CBF)缺陷 侧支功能受损。这些数据有力地表明，CGRP拮抗剂可能会加剧巧合 或叠加的缺血事件，特别是在偏头痛患者的慢性预防上。因此，我们最重要的是 目的是确定降钙素基因相关肽拮抗剂的脑血管安全性，并细化目标人群以缓解 风险。为此，我们建议研究降钙素基因相关肽拮抗剂对局灶性脑缺血的危险性增加。 血管危险因素的缺失(目标1)或存在(目标2)，并阐明其机制(目标3)。 目的1将测试Gepant和抗CGRP单抗是否加重局灶性脑缺血 小鼠大脑中动脉闭塞不同时间后的结果。我们将建立剂量-反应，作用持续时间， 延长降钙素基因相关肽拮抗作用。目标2将测试是否同时存在血管危险因素(衰老、 糖尿病、高血压、有先兆的偏头痛)会加剧降钙素基因相关肽拮抗的风险。我们还将确定 抗CGRP单抗可穿透血脑屏障。目标3将测试CGRP拮抗作用 使用尖端光学成像技术，在活体内损害脑侧支和软膜及穿透动脉的功能 工具(激光散斑流量计、动态光散射光学相干层析成像、双光子显微镜)。 所有实验都将使用男性和女性，特别强调严谨性和可重复性。 数以百万计的偏头痛患者很快将接受CGRP拮抗剂治疗。我们必须更好地理解 以客观、无偏见的方式评估与这类药物相关的脑血管风险。这是一项使命 不太可能由该行业进行或资助，应该信任由NIH资助的实验室 没有利益冲突。我们实验室在偏头痛和中风方面都有长期的记录。调查组 包括核磁共振、光学成像和偏头痛病理生理学和治疗方面的专家。所有建议的方法都是 在日常使用中。因此，我们认为，我们处于独特的地位，能够满足这一迫切的未得到满足的需求。

Small molecule calcitonin gene-related peptide (CGRP) receptor antagonists (“gepants”) and anti-CGRP or anti- CGRP-receptor monoclonal antibodies (“nezumabs”) are novel treatments for migraine. However, endogenous CGRP is among the most potent vasodilator molecules, and CGRP-mediated vasodilation is a critical rescue mechanism in cerebral ischemia. Therefore, CGRP antagonism may increase cerebrovascular event risk in migraineurs. Despite this obvious concern, the magnitude of unmet need in the migraine field has propelled the clinical development of CGRP antagonists despite case reports of vascular complications. We recently reported that gepants worsen the outcome after brief middle cerebral artery occlusion (MCAO) mimicking transient ischemic attack in mice (Mulder et al. Ann Neurol, 2020). Gepant arm was significantly more likely to develop infarcts compared with controls. Upon longer MCAO, infarct volumes, neurological deficits and mortality were also higher in the gepant arm. Worse cerebral blood flow (CBF) deficits during MCAO implicated impaired collateral function. These data strongly suggest that CGRP antagonists might exacerbate coincidental or superimposed ischemic events, especially in migraineurs on chronic prophylaxis. Therefore, our overarching goal is to define the cerebrovascular safety of CGRP antagonism and refine the target population to mitigate the risk. To this end, we propose to examine the risk increment with CGRP antagonism in focal cerebral ischemia in the absence (Aim 1) or presence of vascular risk factors (Aim 2), and elucidate the mechanisms (Aim 3). Aim 1 will test whether a gepant and an anti-CGRP monoclonal antibody worsen focal cerebral ischemic outcomes after various durations of MCAO in mice. We will establish the dose-response, the duration of effect, and the effect of prolonged CGRP antagonism. Aim 2 will test whether comorbid vascular risk factors (aging, diabetes, hypertension, migraine with aura) exacerbate the risk of CGRP antagonism. We will also determine blood-brain barrier penetration of the anti-CGRP monoclonal antibody. Aim 3 will test whether CGRP antagonism impairs cerebral collaterals and pial and penetrating arterial function, in vivo, using cutting-edge optical imaging tools (laser speckle flowmetry, dynamic light scattering optical coherence tomography, two-photon microscopy). All experiments will use both males and females with particular emphasis on rigor and reproducibility. Millions of migraineurs are soon going to be receiving CGRP antagonists. It is imperative to better understand the cerebrovascular risk associated with this class of drugs in an objective, bias-free manner. This is a mission unlikely to be carried out or funded by the industry and should be trusted into the hands of NIH-funded labs with no conflict of interest. Our laboratory has a long track record in both migraine and stroke. The investigative team includes experts in MRI, optical imaging and migraine pathophysiology and therapies. All proposed methods are in daily use. Therefore, we believe we are uniquely positioned to address this urgent unmet need.