Migraine Prophylaxis, Ischemic Depolarizations, and Stroke Outcomes in Mice

Abstract

Background and Purpose Migraine with aura is an established stroke risk factor, and excitatory mechanisms such as spreading depression are implicated in the pathogenesis of both migraine and stroke. Spontaneous spreading depression waves originate within the peri-infarct tissue and exacerbate the metabolic mismatch during focal cerebral ischemia. Genetically enhanced spreading depression susceptibility facilitates anoxic depolarizations and peri-infarct spreading depressions and accelerates infarct growth, suggesting that susceptibility to spreading depression is a critical determinant of vulnerability to ischemic injury. Because chronic treatment with migraine prophylactic drugs suppresses spreading depression susceptibility, we tested whether migraine prophylaxis can also suppress ischemic depolarizations and improve stroke outcome. Methods We measured the cortical susceptibility to spreading depression and ischemic depolarizations, and determined tissue and neurological outcome after middle cerebral artery occlusion in wild type and familial hemiplegic migraine type 1 knock-in mice treated with vehicle, topiramate or lamotrigine daily for 7 weeks or as a single dose shortly before testing. Results Chronic treatment with topiramate or lamotrigine reduces the susceptibility to KCl- or electrical stimulation-induced spreading depressions as well as ischemic depolarizations in both wild-type and familial hemiplegic migraine type 1 mutant mice. Consequently, both tissue and neurological outcomes are improved. Notably, treatment with a single dose of either drug is ineffective. Conclusions These data underscore the importance of hyperexcitability as a mechanism for increased stroke risk in migraineurs, and suggest that migraine prophylaxis may not only prevent migraine attacks but also protect migraineurs against ischemic injury.

Vagus nerve stimulation inhibits cortical spreading depression

“…The degree of CSD suppression by VNS was comparable to suppression by migraine prophylactic drugs previously demonstrated in the same experimental paradigm [8; 13; 25]. We demonstrate the efficacy using both non-invasive transcutaneous and invasive VNS approaches currently approved for clinical use, employing experimental techniques accepted as the gold standard to assess CSD susceptibility, and under full systemic physiological monitoring to eliminate potential confounders [7].…”

“…Experimental data also suggest that iVNS (20 Hz, 30 sec trains of 0.3–0.5 ms/0.5 mA square pulses, every 5 minutes for 1–3h) reduces infarct size and improves functional outcome in animal models of focal cerebral ischemia [3; 33]. Taken together, our data implicate SD inhibition as one mechanism by which VNS may improve stroke outcomes as well [25; 60]. …”

Cerebellar Hypoperfusion in Migraine Attack: Incidence and Significance

“…Similar findings have been reported in an animal study. 34 Thus, typical episodes with regularly experienced aura symptoms may reflect benign oligemia not related to tissue damage, while prolonged and severe hypoxic episodes may ultimately induce parenchymal damage, which was not observed in our cohort. This study has some limitations.…”

Modulation of intracranial meningeal nociceptor activity by cortical spreading depression: a reassessment

“…A paradigm using the elicitation of a train of CSD events is often used in preclinical studies to explore the effects of anti-migraine agents. Recent studies, employing this paradigm, have found that agents used in migraine prophylaxis can suppress the frequency of CSD events within a train (Ayata et al 2006;Eikermann-Haerter et al 2015). Given that multiple CSDs do not exert an additive nociceptive effect compared with a single CSD event, we propose that a reduction in the number of CSD episodes within a train may not serve as a good predictor of a drug's anti-migraine effect.…”