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Migraine is a leading cause of disability in more than one billion people worldwide, yet it remains universally underappreciated, even by individuals with the condition. Among other shortcomings, current treatments (often repurposed agents) have limited efficacy and potential adverse effects, leading to low treatment adherence. After the introduction of agents that target the calcitonin gene-related peptide pathway, another new drug class, the ditans — a group of selective serotonin 5-HT1F receptor agonists — has just reached the international market. Here, we review preclinical studies from the late 1990s and more recent clinical research that contributed to the development of the ditans and led to their approval for acute migraine treatment by the US Food and Drug Administration and the European Medicines Agency. Ditans are a recently developed drug class for the treatment of acute migraine. In this Review, the authors provide an overview of ditan development, from the initial rationale to the clinical studies that led to the recent FDA approval of the first ditan. Key points: Various animal studies have shown that selective agonists for the serotonin 5-HT1F receptor can reduce signals from an activated trigeminovascular system, thereby highlighting the receptor as an attractive target for symptomatic treatment of migraine. Long-term clinical studies involving two ditans — a group of 5-HT1F agonists — have provided class I evidence that lasmiditan, the first ditan, is both effective and safe in the symptomatic treatment of migraine. The 5-HT1F receptor is expressed by cells within the brain parenchyma, as well as by the trigeminal neurons, but not in vascular smooth muscle, suggesting that ditans act through neuropeptide release leading to acute headache relief, rather than via potential vasoactive properties, such as vasodilatation. Dizziness is the most common adverse event of lasmiditan; thus people should not drive for 8 h after taking lasmiditan. Development of novel ditans that do not cross the blood–brain barrier is expected to result in better tolerability and improved clinical use. [ABSTRACT FROM AUTHOR]

Familial hemiplegic migraine type 1, a monogenic migraine variant with aura, is linked to gain-of-function mutations in the CACNA1A gene encoding CaV2.1 channels. The S218L mutation causes severe channel dysfunction, and paroxysmal migraine attacks can be accompanied by seizures, coma, and hemiplegia; patients expressing the R192Q mutation exhibit hemiplegia only. Familial hemiplegic migraine knock-in mice expressing the S218L or R192Q mutation are highly susceptible to cortical spreading depression, the electrophysiological surrogate for migraine aura, and develop severe and prolonged motor deficits after spreading depression. The S218L mutants also develop coma and seizures and sometimes die. To investigate underlying mechanisms for these symptoms, we used multielectrode electrophysiological recordings, diffusion-weighted magnetic resonance imaging, and c-fos immunohistochemistry to trace spreading depression propagation into subcortical structures. We showed that unlike the wild type, cortical spreading depression readily propagated into subcortical structures in both familial hemiplegic migraine type 1 mutants. Whereas the facilitated subcortical spread appeared limited to the striatum in R192Q, hippocampal and thalamic spread was detected in the S218L mutants with an allele-dosage effect. Both strains exhibited increased susceptibility to subcortical spreading depression and reverberating spreading depression waves. Altogether, these data show that spreading depression propagates between cortex, basal ganglia, diencephalon, and hippocampus in genetically susceptible brains, which could explain the prolonged hemiplegia, coma, and seizure phenotype in this variant of migraine with aura. [ABSTRACT FROM AUTHOR]

Migraine is among the most prevalent neurological disorders worldwide, afflicting up to 16% of the population. Because it mostly affects patients between the most productive ages of 25 and 50 years, migraine costs employers more than US$13 billion per year in reduced productivity and missed days. It is therefore important to prevent and treat migraine attacks. Triptans were introduced in the early 1990s and effectively alleviate symptoms in most patients. Their success was based on the existence of the operational hypothesis implicating the trigemino-vascular system. Prophylactic medications have been available since beta-blockers, followed by agents belonging to other therapeutic classes. Most of them were found serendipitously to be effective. However, progress in the development of preventative agents has been hampered by the lack of animal models mimicking the early events of migraine pathophysiology. This review will examine how a recent theory on the origin of migraine attacks is likely to lead to the development of new animal models. [ABSTRACT FROM AUTHOR]

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 with wild-type mice, 2 FHM 1 mutant mouse strains developed earlier onset of anoxic depolarization and more frequent peri-infarct depolarizations associated with rapid expausion of infarct core on diffusion-weighted magnetic resonance imaging 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. [ABSTRACT FROM AUTHOR]

Background: Migraine is a disabling chronic episodic disorder. Attack frequency progressively increases in some patients. Incremental cortical excitability has been implicated as a mechanism underlying progression. Cortical spreading depression (CSD) is the electrophysiological event underlying migraine aura, and a headache trigger .We hypothesized that CSD events during frequent migraine attacks condition the cortex to increase the susceptibility to further attacks. Methods: A single daily CSD was induced for 1 or 2 weeks in mouse frontal cortex; contralateral hemisphere served as sham control. At the end of CSD conditioning, occipital CSD susceptibility was determined by measuring the frequency of CSDs evoked by topical KCl application. Results: Sham hemispheres developed 8.4 ± 0.3 CSDs/hour, and did not significantly differ from naïve controls without prior cranial surgery (9.3 ± 0.4 CSDs/hour). After 2 but not 1 week of daily CSD conditioning, CSD frequency (4.9± 0.3 CSDs/hour) as well as the duration and propagation speed were reduced significantly in the conditioned hemispheres. Histopathological examination revealed marked reactive astrocytosis without neuronal injury throughout the conditioned cortex after 2 weeks, temporally associated with CSD susceptibility. Conclusions: These data do not support the hypothesis that frequent migraine attacks predispose the brain to further attacks by enhancing tissue susceptibility to CSD. [ABSTRACT FROM AUTHOR]

Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura that is associated with hemiparesis. As with other types of migraine, it affects women more frequently than men. FHM1 is caused by mutations in the CACNA1A gene, which encodes the alpha1A subunit of Cav2.1 channels; the R192Q mutation in CACNA1A causes a mild form of FHM1, whereas the S218L mutation causes a severe, often lethal phenotype. Spreading depression (SD), a slowly propagating neuronal and glial cell depolarization that leads to depression of neuronal activity, is the most likely cause of migraine aura. Here, we have shown that transgenic mice expressing R192Q or S218L FHM1 mutations have increased SD frequency and propagation speed; enhanced corticostriatal propagation; and, similar to the human FHM1 phenotype, more severe and prolonged post-SD neurological deficits. The susceptibility to SD and neurological deficits is affected by allele dosage and is higher in S218L than R192Q mutants. Further, female S218L and R192Q mutant mice were more susceptible to SD and neurological deficits than males. This sex difference was abrogated by ovariectomy and senescence and was partially restored by estrogen replacement, implicating ovarian hormones in the observed sex differences in humans with FHM1. These findings demonstrate that genetic and hormonal factors modulate susceptibility to SD and neurological deficits in FHM1 mutant mice, providing a potential mechanism for the phenotypic diversity of human migraine and aura. [ABSTRACT FROM AUTHOR]