Investigating the basic mechanisms linking migraine and stroke

描述（由申请人提供）：偏头痛是最常见的衰弱性神经系统疾病。它曾经被认为是相对无害的，但现在人们知道它会增加中风的风险，尤其是女性，每年导致1500多例死亡。这一重大临床问题的原因尚不清楚。我们将试图通过关注这些疾病之间的联系特征来理解它。皮层扩张性抑制（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可能是偏头痛先兆的发病机制，CSD和PID均加重脑卒中。对偏头痛的易感性与对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，与患偏头痛的男女比例为3:1一致。表达导致严重偏头痛变异基因的小鼠也有较低的CSD阈值。我们的建议是，增加CSD风险的相同因素也有利于PID，因此可能解释偏头痛卒中发生率增加的原因。我们将用两组相关的实验来检验这一假设。第一项研究将检查CSD在孤立情况下被认为是良性的可能性，在慢性基础上实际上可能是有害的，特别是当与基于性别和遗传的偏头痛易感性相结合时。我们将比较雌性小鼠和雄性小鼠，偏头痛转基因小鼠和对照组，看看长期的CSD是否会导致类似中风的损伤。如果确实如此，它就可以解释偏头痛患者在影像学上看到的高比率的亚临床中风样变化。第二组实验将测试偏头痛的倾向（以及CSD）也会增加PID合并中风的风险这一命题。我们将在雌性、雄性、偏头痛转基因和野生型小鼠中诱导中风，以观察偏头痛易感性是否会增加PID的数量和严重程度，增加中风的大小，并恶化中风的恢复。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的预防药物，是否也可以预防PID和中风相关的损害。我们将结合先进的成像、神经元记录、行为和组织检查来解决所有这些临床重要问题。

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.