Migraine mutations increase stroke vulnerability by facilitating ischemic depolarizations.
Migraine mutations increase stroke vulnerability by facilitating ischemic depolarizations.
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DOI：
10.1161/circulationaha.111.045096
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发表时间：
2012-01-17
期刊：
影响因子：
37.8
通讯作者：
Ayata C
中科院分区：
文献类型：
--
作者：
Eikermann-Haerter K;Lee JH;Yuzawa I;Liu CH;Zhou Z;Shin HK;Zheng Y;Qin T;Kurth T;Waeber C;Ferrari MD;van den Maagdenberg AM;Moskowitz MA;Ayata C
偏头痛是中风的独立危险因素。这种关联的机制尚不清楚。家族性偏瘫性偏头痛 (FHM) 是一种偏头痛亚型，也会增加中风风险，由于具有共同的先兆和头痛特征、触发因素和潜在的谷氨酸能机制，因此是常见偏头痛表型的有用模型。在这里，我们发现 CaV2.1 电压门控 Ca2+ 通道中的 FHM 1 型 (FHM1) 突变使大脑更容易发生缺血性中风。与野生型相比，两种 FHM1 突变小鼠品系出现更早的缺氧去极化和更频繁的梗死周围去极化，这与扩散加权 MRI 上梗塞核心的快速扩张和激光散斑流量计上更大的灌注不足相关。突变体中组织存活所需的脑血流量更高，导致梗死且缺血程度较轻。结果，突变体在中风后出现了更大的梗塞和更差的神经系统结果，而谷氨酸受体拮抗剂可以选择性地减弱这些结果。我们认为，与抑郁症蔓延类似，对缺血性去极化的敏感性增强，使偏头痛患者在轻度缺血事件期间容易发生梗死，从而增加中风风险。
Migraine is an independent risk factor for stroke. Mechanisms underlying this association are unclear. Familial hemiplegic migraine (FHM), a migraine subtype that also carries an increased stroke risk, is a useful model for common migraine phenotypes because of shared aura and headache features, trigger factors, and underlying glutamatergic mechanisms. Here, we show that FHM type 1 (FHM1) mutations in CaV2.1 voltage-gated Ca2+ channels render the brain more vulnerable to ischemic stroke. Compared to wild-type, two FHM1 mutant mouse strains developed earlier onset of anoxic depolarization and more frequent peri-infarct depolarizations, associated with rapid expansion of infarct core on diffusion-weighted MRI and larger perfusion deficits on laser speckle flowmetry. Cerebral blood flow required for tissue survival was higher in the mutants, leading to infarction with milder ischemia. As a result, mutants developed larger infarcts and worse neurological outcomes after stroke, which were selectively attenuated by a glutamate receptor antagonist. We propose that enhanced susceptibility to ischemic depolarizations akin to spreading depression predisposes migraineurs to infarction during mild ischemic events, thereby increasing the stroke risk.