MIGRAINE DRUG PROPHYLAXIS

描述（由申请人提供）：20%的人口患有偏头痛，女性发病率是女性的3倍。了解偏头痛的机制导致了最近更有效的急性药物的发展。相比之下，根据经验发现的预防性药物属于不同的治疗类别（丙戊酸酯、托吡酯、阿米替林、心得安和甲基塞吉特），每种药物只能抑制大约50%的发作。由于预防性治疗适用于每月出现3天以上头痛相关残疾的患者，因此必须首先确定相关的组织或药物靶点，以改善偏头痛预防药物。在初步实验中，我们发现慢性每日服用每种药物可抑制皮质扩张性抑制（CSD）的易感性，CSD是一种鲜为人知的缓慢传播的电生理事件。在该模型中，急性治疗无效，初步实验显示较长期治疗（2-3个月）更有效。基于这些观察结果，我们提出了4个具体目标来验证预防性药物抑制CSD作为偏头痛预防的基本机制的假设。据我们所知，这是第一个确定偏头痛预防的一致目标。第一个目标是建立该模型中迄今为止成功测试的药物的剂量和时间特征，并扩大测试药物的列表，试图建立动物和人类药物治疗之间的对应关系，并验证啮齿动物模型。Aim 2将以这些信息为基础，确定大脑皮层内基因表达的重叠模式是否解释了在使用Aim 1中确定的最佳剂量和时间进行慢性治疗后抑制CSD的重要共同机制。为了改善偏头痛亚型（家族性偏瘫偏头痛）的治疗，Aim 3提出确定迄今为止测试的有效药物是否不仅在野生型动物中抑制CSD阈值，而且在表达编码Cav2.1 （P/Q钙通道）α -1亚基的敲入人类突变的基因工程小鼠中也抑制CSD阈值。这种突变导致严重的偏头痛亚型（FHM1），并使突变小鼠比野生型更容易患CSD。越来越多的证据表明性激素是皮质兴奋性的重要决定因素。目的4提出建立在初步数据的基础上，表明雌激素停药（而不是雌激素给药本身）增加了大鼠皮层对CSD的易感性。我们建议探索雌激素在多大程度上有助于大鼠的CSD阈值，因此，可能在成年女性中也是如此。综上所述，这些目标是寻求影响我们对偏头痛及其预防的理解的新信息，以及评估一种潜在有用的动物模型的有效性和优点的数据，以筛选作为偏头痛预防候选药物。

DESCRIPTION (provided by applicant): Migraine afflicts 20% of the population and is 3x more common in females. Understanding the mechanisms of migraine pain has led to the recent development of more effective acute medications. In contrast, prophylactic drugs belonging to distinct therapeutic classes (valproate, topiramate, amitriptyline, propranolol and methysergide) have been discovered empirically, and each of them only suppresses attacks by approximately 50%. Because prophylactic therapy is indicated in patients with 3+ days/month of headache-related disability, it is essential to improve migraine-preventing agents by first identifying relevant tissue or drug targets. In preliminary experiments, we discovered that chronic daily administration of each drug suppressed the susceptibility to cortical spreading depression (CSD), a poorly understood, slowly propagating electrophysiological event. Acute treatments were ineffective in this model and longer-term treatments (2-3 months) appeared more effective in preliminary experiments. Based on these observations, we propose 4 specific aims to test the hypothesis that prophylactic drugs suppress CSD as a fundamental mechanism contributing to migraine prophylaxis. To our knowledge, this is the first coherent target identified for migraine prophylaxis. The first aim proposes to establish the dose and time characteristics for drugs successfully tested so far in this model, and to expand the list of tested drugs in an attempt to establish a correspondence between animal and human drug treatments and to validate the rodent model. Aim 2 will build upon this information to determine whether overlapping patterns of gene expression within cerebral cortex explain common mechanisms important for CSD suppression after chronic treatments using optimized doses and times determined in Aim 1. In order to improve treatment for a migraine subtype (Familial Hemiplegic Migrainel), Aim 3 proposes to determine whether the effective drugs tested to date suppress CSD threshold not only in wild type animals, but also in genetically-engineered mice expressing a knock-in human mutation encoding the alpha-1 subunit of Cav2.1 (P/Q calcium channel). This mutation causes a severe migraine subtype (FHM1) and renders mutant mice more susceptible to CSD than wild type. There is emerging evidence implicating sex hormones as an important determinant of cortical excitability. Aim 4 proposes to build on preliminary data showing that estrogen withdrawal (but not estrogen administration itself) increases the susceptibility of rat cortex to CSD. We propose to explore the extent to which estrogen contributes to CSD threshold in rats, and therefore, possibly in adult human females as well. Taken together, these aims are seeking novel information impacting our understanding of migraine and its prophylaxis, and data to evaluate the validity and merits of a potentially useful animal model for screening drugs as candidates for migraine prophylaxis.