Investigating the basic mechanisms linking migraine and stroke

描述（由申请人提供）：偏头痛是最常见的使人衰弱的神经系统疾病。曾经被认为是相对良性的，现在已知它会增加中风的风险，特别是在女性中，每年造成1500多人死亡。这一重大临床问题的原因尚不清楚。我们将试图通过关注与这些疾病相关的特征来理解它。皮层扩散性抑制（CSD）和梗死周围去极化（PID）是几乎相同的兴奋波，在大脑表面移动。CSD是偏头痛先兆的可能机制，CSD和PID都使卒中恶化。偏头痛的易感性与CSD的易感性相关：我们已经表明，雌性小鼠诱导CSD的阈值较低，与偏头痛女性与男性的3：1比例一致。表达导致严重偏头痛变异基因的小鼠也具有较低的CSD阈值。我们的建议是，增加CSD风险的相同因素也有利于PID，因此可能导致偏头痛中风率增加。我们将用两组相关的实验来检验这个假设。第一个将研究CSD的可能性，孤立地认为是良性的，实际上可能是有害的慢性基础上，特别是当与基于性别和遗传倾向偏头痛配对。我们将比较雌性小鼠和雄性小鼠，以及偏头痛转基因小鼠和对照小鼠，以观察长期CSD是否会引起中风样损害。如果是这样的话，它可以解释偏头痛患者影像学上亚临床卒中样改变的高发生率。第二组实验将测试偏头痛（以及CSD）的倾向也会增加PID伴中风的风险。我们将在雌性、雄性、偏头痛转基因小鼠和野生型小鼠中诱导中风，以观察偏头痛易感性是否增加PID的数量和严重程度，增加中风大小，并阻碍中风恢复。我们还将测试美金刚，一种抑制CSD的药物，我们已经确定为偏头痛预防药，是否也可以防止PID和中风相关的损害。我们将使用先进的成像，神经元记录，行为和组织检查的组合来解决所有这些临床上重要的问题。 公共卫生相关性：这一建议直接解决了一个严重的临床问题的技术，应提供具体的机械和临床可操作的信息。我们的实验应该促进对偏头痛和中风的理解，特别是增加女性风险的激素和遗传因素，并在此过程中为高危患者的治疗提供具体建议。

DESCRIPTION (provided by applicant): Migraine is the most common debilitating neurological disorder. Once considered relatively benign, it is now known to increase the risk for stroke, especially in women, accounting for 1500 excess deaths a year. The reason for this significant clinical problem is unknown. We will attempt to understand it by focusing on features that link the disorders. Cortical spreading depression (CSD) and peri-infarct depolarization (PID) are nearly identical waves of excitation that move across the brain surface. CSD is the likely mechanism of the migraine aura, and both CSD and PID worsen stroke. Susceptibility to migraine is associated with a susceptibility to CSD: we have shown that female mice have a lower threshold for induction of CSD, in line with the 3:1 ratio of women to men with migraine. And mice expressing genes that cause severe variants of migraine also have lower CSD thresholds. Our proposal is that the same factors which increase the risk of CSD also favor PID, and thus may account for the increased rate of stroke in migraine. We will test this assumption with two related sets of experiments. The first will examine the possibility that CSD, considered benign in isolation, may actually be harmful on a chronic basis, especially when paired with sex-based and genetic predisposition to migraine. We will compare female to male mice, and migraine transgenic mice to controls, to see whether long term CSD causes stroke-like damage. If it does, it could explain the high rate of subclinical stroke-like changes seen on imaging of migraine patients. The second set of experiments will test the proposition that the tendency to migraine (and thus CSD) also confers an increased risk of PID with stroke. We will induce stroke in female, male, migraine transgenic, and wild type mice to see if migraine susceptibility increases the number and severity of PID, increases stroke size, and worsens stroke recovery. We will also test whether memantine, a drug that inhibits CSD, and that we have identified as a migraine preventive, can also protect against PID and stroke related damage. We will use a combination of advanced imaging, neuronal recordings, behavior, and tissue examination to address all of these clinically important questions. PUBLIC HEALTH RELEVANCE: This proposal directly addresses a serious clinical problem with techniques that should provide both mechanistically specific and clinically-actionable information. Our experiments should advance the understanding of both migraine and stroke, especially the hormonal and genetic factors that increase risks in women, and in doing so generate concrete recommendations for the treatment of at-risk patients.