No central action of CGRP antagonising drugs in the GTN mouse model of migraine
No central action of CGRP antagonising drugs in the GTN mouse model of migraine
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DOI：
10.1177/0333102420914913
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发表时间：
2020-03-29
期刊：
影响因子：
4.9
通讯作者：
Kristensen, David M.
中科院分区：
文献类型：
--
作者：
Christensen, Sarah L.;Ernstsen, Charlotte;Kristensen, David M.
在临床上，降钙素基因相关肽拮抗剂被认为是治疗偏头痛的有效药物，但其作用部位存在争议。这些化合物中只有一小部分能通过血脑屏障进入中枢神经系统。不管怎样，一直有人认为中枢神经系统是起作用的部位。在这里，我们通过脑室内注射降钙素基因相关肽拮抗剂绕过血脑屏障来验证这一假设。方法采用三硝酸甘油（GTN）小鼠模型，该模型对特定偏头痛药物的反应得到了很好的验证。降钙素基因相关肽受体拮抗剂olcegepant和降钙素基因相关肽单克隆抗体ALD405分别腹腔或脑室内给药。结果测量为皮肤机械性异常性疼痛。结果在第1天，对照组腹腔注射孕酮+ GTN，其50%戒断阈值为1.2 g，对照组腹腔注射安慰剂+ GTN，戒断阈值为0.3 g （p < 0.001）。同样，在ALD405 + GTN组中，小鼠的阈值为1.2 g，而安慰剂+ GTN组为0.2 g （p < 0.001）。然而，当脑室内给药时，这两种药物都无效，因为对照组和活性组具有相同的机械敏感性阈值，分别为0.2 g对0.1 g， 0.1 g对0.1 g olgegepant和ALD405（两种情况下p均为0.99）。讨论在偏头痛小鼠模型中，孕激素和单克隆抗体ALD405的作用位点在血脑屏障外。很可能这些结果可以推广到所有的基因和抗体，并且结果与人类偏头痛有关。
IntroductionClinically, calcitonin gene-related peptide antagonising drugs are recognized as effective in migraine treatment, but their site of action is debated. Only a small fraction of these compounds pass the blood-brain barrier and accesses the central nervous system. Regardless, it has been argued that the central nervous system is the site of action. Here, we test this hypothesis by bypassing the blood-brain barrier through intracerebroventricular injection of calcitonin gene-related peptide antagonising drugs.MethodsWe used the glyceryl trinitrate (GTN) mouse model, which is well validated by its response to specific migraine drugs. The calcitonin gene-related peptide receptor antagonist olcegepant and the calcitonin gene-related peptide monoclonal antibody ALD405 were administered either intraperitoneally or intracerebroventricularly. The outcome measure was cutaneous mechanical allodynia.ResultsMice given olcegepant intraperitoneally + GTN on day 1 had a mean 50% withdrawal threshold of 1.2 g in contrast to mice receiving placebo + GTN, which had a threshold of 0.3 g (p < 0.001). Similarly, in the ALD405 + GTN group, mice had thresholds of 1.2 g versus 0.2 g in the placebo + GTN group (p < 0.001). However, both drugs were ineffective when delivered intracerebroventricularly, as control and active groups had identical mechanical sensitivity thresholds, 0.2 g versus 0.1 g and 0.1 g versus 0.1 g for olcegepant and ALD405, respectively (p > 0.99 in both cases).DiscussionThe site of action of olcegepant and of the monoclonal antibody ALD405 is outside the blood-brain barrier in this mouse model of migraine. It is likely that these results can be generalised to all gepants and all antibodies and that the results are relevant for human migraine.