MIGRAINE DRUG PROPHYLAXIS

描述（由申请人提供）：偏头痛困扰20%的人口，女性中的发病率是男性的3倍。了解偏头痛的机制导致最近开发出更有效的急性药物。相反，属于不同治疗类别的预防性药物（丙戊酸盐、托吡酯、阿米替林、普萘洛尔和麦角新碱）是根据经验发现的，它们中的每一种都只能抑制大约50%的发作。由于预防性治疗适用于头痛相关残疾3天/月以上的患者，因此必须首先确定相关组织或药物靶点，以改善偏头痛预防药物。在初步实验中，我们发现，慢性每日给药的每种药物抑制的易感性皮层扩散性抑制（CSD），一个知之甚少，传播缓慢的电生理事件。急性治疗在该模型中无效，长期治疗（2-3个月）在初步实验中似乎更有效。基于这些观察结果，我们提出了4个具体的目标来检验预防性药物抑制CSD作为偏头痛预防的基本机制的假设。据我们所知，这是第一个明确的偏头痛预防目标。第一个目标是建立迄今为止在该模型中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，以尝试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将建立在此信息的基础上，以确定大脑皮层内的基因表达的重叠模式是否解释了使用目标1中确定的优化剂量和时间进行慢性治疗后CSD抑制的重要常见机制。为了改善偏头痛亚型（家族性偏瘫偏头痛）的治疗，目的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）的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（FHM 1），并使突变小鼠比野生型更容易受到CSD的影响。有新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表明，雌激素戒断（而不是雌激素管理本身）增加大鼠皮质CSD的易感性。我们建议探讨雌激素在多大程度上有助于CSD阈值在大鼠中，因此，可能在成年女性以及。总之，这些目标是寻求新的信息，影响我们对偏头痛及其预防的理解，以及评估潜在有用的动物模型的有效性和优点的数据，以筛选药物作为偏头痛预防的候选药物。

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.