Headache Research Unit, GIGA-Neurosciences and Department of Neurology, Liège University, CHU Sart Tilman B36, T4, +1, B-4000, Liège, Belgium.
Neurobiol Dis. 2011 Feb;41(2):430-5. doi: 10.1016/j.nbd.2010.10.014. Epub 2010 Oct 23.
Cortical spreading depression (CSD) is the most likely cause of the migraine aura. Drugs with distinct pharmacological properties are effective in the preventive treatment of migraine. To test the hypothesis that their common denominator might be suppression of CSD we studied in rats the effect of three drugs used in migraine prevention: lamotrigine which is selectively effective on the aura but not on the headache, valproate and riboflavin which have a non-selective effect. Rats received for 4 weeks daily intraperitoneal injections of one of the three drugs. For valproate and riboflavin we used saline as control, for lamotrigine its vehicle dimethyl sulfoxide. After treatment, cortical spreading depressions were elicited for 2h by occipital KCl application. We measured CSD frequency, its propagation between a posterior (parieto-occipital) and an anterior (frontal) electrode, and number of Fos-immunoreactive nuclei in frontal cortex. Lamotrigine suppressed CSDs by 37% and 60% at posterior and anterior electrodes. Valproate had no effect on posterior CSDs, but reduced anterior ones by 32% and slowed propagation velocity. Riboflavin had no significant effect at neither recording site. Frontal Fos expression was decreased after lamotrigine and valproate, but not after riboflavin. Serum levels of administered drugs were within the range of those usually effective in patients. Our study shows that preventive anti-migraine drugs have differential effects on CSD. Lamotrigine has a marked suppressive effect which correlates with its rather selective action on the migraine aura. Valproate and riboflavin have no effect on the triggering of CSD, although they are effective in migraine without aura. Taken together, these results are compatible with a causal role of CSD in migraine with aura, but not in migraine without aura.
皮质扩散性抑制（CSD）是偏头痛先兆最可能的原因。具有明显药理学特性的药物在偏头痛的预防性治疗中有效。为了检验它们的共同作用机制可能是抑制 CSD 的假说，我们在大鼠中研究了三种用于偏头痛预防的药物的效果：拉莫三嗪，它对先兆有选择性作用，而对头痛没有作用；丙戊酸和核黄素，它们有非选择性作用。大鼠接受了 4 周的每日腹腔注射三种药物之一。对于丙戊酸和核黄素，我们使用生理盐水作为对照，对于拉莫三嗪，使用其载体二甲亚砜。治疗后，通过枕部 KCl 应用诱发皮质扩散性抑制 2 小时。我们测量了 CSD 频率、在后电极和前电极之间的传播，以及额皮质中 Fos 免疫反应性核的数量。拉莫三嗪使后电极和前电极的 CSD 分别减少了 37%和 60%。丙戊酸对后电极的 CSD 没有影响，但减少了前电极的 CSD 32%，并减慢了传播速度。核黄素在两个记录部位均无显著作用。拉莫三嗪和丙戊酸后额皮质的 Fos 表达减少，但核黄素无明显作用。给予药物的血清水平在通常对患者有效的范围内。我们的研究表明，预防性抗偏头痛药物对 CSD 有不同的影响。拉莫三嗪具有显著的抑制作用，这与其对偏头痛先兆的选择性作用相关。丙戊酸和核黄素对 CSD 的触发没有影响，尽管它们对无先兆偏头痛有效。总的来说，这些结果与 CSD 在有先兆偏头痛中起因果作用的假说一致，但在无先兆偏头痛中则不然。
