Lamotrigine in the Prevention of Migraine With Aura

A Narrative Review

Dan Buch, MD; Hugues Chabriat, MD, PhD

Disclosures

Headache. 2019;59(8):1187-1197. 

In This Article

Voltage-gated Ionic Channels are Involved in Different Subtypes of MA

Gain of function mutations of the CACNA1A gene, encoding the pore-forming α-subunit of the neuronal voltage-gated Cav2.1 (P/Q type) channels were shown to cause Familial Hemiplegic Migraine type 1 (FHM1). These ionic channels are predominantly localized at the presynaptic terminals of cortical glutamatergic neurons where they play an important role in controlling glutamate release. Mutations in the ATP1A2 gene, encoding a subunit of the NA+/K+ ATPase heavily expressed in astrocytes are involved in FHM type 2 (FHM2). They are presumably responsible for increased resting potentials of cerebral astrocytes. Mutations in the SCN1A gene, encoding a sodium channel α-subunit (NaV1.1) that plays an important role in the generation of neuronal action potentials, cause FHM type 3 (FHM3) of close phenotype.[19] Additionally, a dominant-negative mutation in the TRESK potassium channel, a 2-pore domain (K2P) potassium channel, encoded by KCNK18, has recently been reported in typical familial MA.[20] K2P channels are expressed throughout the central nervous system and have a key role in controlling neuronal resting membrane potential and neuronal excitability.[21] In animal models related to these genetic alterations, a reduced threshold for triggering CSD and a significant increase of glutamate release were found associated with an increased neuronal excitability at the cerebral cortex level and at neuromuscular junctions at rest.[22] The involvement of voltage-gated ionic channels is further demonstrated by the reduced threshold to trigger CSD experimentally using selective voltage-gated calcium channel blockers.[23] Induction of repetitive CSD was also reported with drugs that blocks the inactivation of voltage-gated sodium channels.[24,25] In sporadic cases of MA, the involvement of ionic channels cannot be excluded. Recently, a polymorphism in the CACNA1E gene was detected in sporadic cases of complex MA.[26] The CACNA1E gene encodes a pore-forming subunit of the R-type, (CaV2.3) that is widely expressed in the cortex and muscular presynaptic junctions.[18,27] The R-type channel is involved in spontaneous glutamate release[28] and neuronal rhythmic activity.[29] Moreover, ionic channels might be also involved through other epigenetic mechanisms.[30] Thus, estrogen, whose level can influence the occurrence of spreading depression in animal models and of migraine attacks in women, can regulate the expression and activity of multiple ionic channels in the brain.[31] Finally, voltage-dependent ionic channels are also blocked by a number of validated migraine-preventative medications (see Table 1).

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