Migraine Mutations Increase Stroke Vulnerability by Facilitating Ischemic Depolarizations

Abstract

Background 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. Methods and Results 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. Conclusions 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.

Diffusion-weighted lesions in acute ischaemic stroke patients with migraine

“…A small ischaemic event can then lead to infarction not classifiable as migrainous infarction. Increased susceptibility to infarction from ischaemic events was shown in mice with familial hemiplegic migraine (FHM) and represents a possible explanation of our findings (22). The cortex in FHM mice responded with early anoxic depolarization from small ischaemic events and required a higher cerebral blood flow to maintain neuronal viability, leading to infarction from mild ischaemia.…”

“…The cortex in FHM mice responded with early anoxic depolarization from small ischaemic events and required a higher cerebral blood flow to maintain neuronal viability, leading to infarction from mild ischaemia. With the same ischaemic exposure, they consequently developed larger infarcts and had a worse neurological outcome than mice without FHM (22). The genetic mutations in FHM are not present in all migraineurs (23).…”

Glucose Modulation of Spreading Depression Susceptibility

“…1 Therefore, SD is a potential therapeutic target in migraine and brain injury. 2 Genetic and pharmacological modulation of SD susceptibility is well recognized; [3][4][5][6] however, modulation by systemic physiological factors is poorly understood. Glycemic status in particular is a clinically relevant and modifiable factor in the management of brain injury and migraine.…”

Exploitation of the spreading depolarization-induced cytotoxic edema for high-resolution, 3D mapping of its heterogeneous propagation paths

“…A decreased electrical threshold in mutant mice may thus indicate increased vulnerability to electrical injury rather than a purely functional network anomaly. This notion is further supported by the observation that cerebral blood flow required for tissue survival after middle cerebral artery occlusion was higher in FHM-1 mutant mice compared with WT mice, leading to infarction with milder ischemia (10). Accordingly, mutant mice showed a shorter delay between onset of ischemia and the first SD; subsequent SDs were more frequent.…”