Abstract
Migraine is a highly prevalent neurological disorder imparting a major burden on health care around the world. The primary pathology may be a state of hyperresponsiveness of the nervous system, but the molecular mechanisms are yet to be fully elucidated. We could now be at a watershed moment in this respect, as the genetic loci associated with typical forms of migraine are being revealed. The genetic discoveries are the latest step in the evolution of our understanding of migraine, which was initially considered a cerebrovascular condition, then a neuroinflammatory process and now primarily a neurogenic disorder. Indeed, the genetic findings, which have revealed ion channels and transporter mutations as causative of migraine, are a powerful argument for the neurogenic basis of migraine. Modulations of ion channels leading to amelioration of the migraine 'hyperresponsive' brain represent attractive targets for drug discovery. There lies ahead an exciting and rapidly progressing phase of migraine translational research, and in this review we highlight recent genetic findings and consider how these may affect the future of migraine neurobiology and therapy.
Highlights
Migraine is a common, episodic neurological disorder characterised by severe headaches, and in about onethird of cases it is preceded by a focal, transient neurological phenomenon termed the ‘aura’
Channel mutation, causing a seizure phenotype, activated excitatory hippocampal pyramidal neurons [22]. These findings demonstrate well that the final effect on central nervous system (CNS) excitability is very dependent on whether the predominant effect of a mutation is on inhibitory or excitatory neurons
Summary and future directions Migraine is a multigenic condition in which aberrant ion channels are becoming increasingly implicated in pathogenesis as inducing an altered state of peripheral and central neuronal excitability
Summary
Episodic neurological disorder characterised by severe headaches, and in about onethird of cases it is preceded by a focal, transient neurological phenomenon termed the ‘aura’. The usefulness of FHM genetic studies extends beyond identifying genes responsible for rare migraine subtypes They have provided mechanistic insights into the pathobiology of migraine in general, which seems likely to be a disease related to ionic disturbances with a resultant altered excitability of certain areas of the brain. The identification of KCNK18 and TRPM8 as migraine-associated genes, both highly expressed in sensory neurons, would certainly support the importance of peripheral neurons This in turn has implications for drug design and delivery, since blood-brain barrier permeability may not be a prerequisite for a migraine headache therapeutic drug. Insights gleaned from genetic studies offer novel drug targets and potential prophylactic agents through alterations in neuronal excitability Current prophylactics such as valproate, verapamil, topiramate and lamotrigine are known to have effects on migraine-associated ion channels [62,63].
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