MIGRAINE DRUG PROPHYLAXIS

描述(由申请人提供)：偏头痛困扰着20%的人口，在女性中的发病率是前者的3倍。对偏头痛机制的了解导致了最近更有效的急性药物的发展。相比之下，根据经验发现了属于不同治疗类别的预防药物(丙戊酸盐、托吡酯、阿米替林、普萘洛尔和甲基舍吉德)，每种药物只能抑制大约50%的发作。由于预防治疗适用于有3天/月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，以改进偏头痛预防药物。在初步实验中，我们发现，每种药物的慢性每日给药都抑制了对皮质扩散抑制(CSD)的易感性，CSD是一种知之甚少、传播缓慢的电生理事件。在这个模型中，急性治疗无效，而长期治疗(2-3个月)在初步实验中似乎更有效。基于这些观察，我们提出了4个特定的目标来检验预防药物抑制CSD作为偏头痛预防的基本机制这一假说。据我们所知，这是第一个用于偏头痛预防的连贯靶点。第一个目标是建立到目前为止在这个模型中成功测试的药物的剂量和时间特性，并扩大测试药物的清单，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。目标2将以此信息为基础，确定在使用目标1确定的最佳剂量和时间进行慢性治疗后，大脑皮层内基因表达的重叠模式是否解释了抑制CSD的常见机制。为了改进对偏头痛亚型(家族性偏瘫偏头痛)的治疗，Aim 3建议确定迄今测试的有效药物是否不仅在野生动物中抑制CSD阈值，而且在表达编码Cav2.1(P/Q钙通道)α-1亚单位的敲入人类突变的基因工程小鼠中也抑制CSD阈值。这种突变会导致一种严重的偏头痛亚型(FHM1)，并使突变小鼠比野生小鼠更容易患上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建议建立在初步数据的基础上，表明停用雌激素(但不是雌激素本身)会增加大鼠大脑皮质对CSD的易感性。我们建议探索雌激素对大鼠CSD阈值的影响程度，因此，可能在成年人类女性中也是如此。综上所述，这些目标是寻找影响我们对偏头痛及其预防的理解的新信息，以及评估作为偏头痛预防候选药物的潜在有用动物模型的有效性和优点。

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.