Retigabine, a Kv7.2/Kv7.3-Channel Opener, Attenuates Drug-Induced Seizures in Knock-In Mice Harboring Kcnq2 Mutations

Abstract

The hetero-tetrameric voltage-gated potassium channel Kv7.2/Kv7.3, which is encoded by KCNQ2 and KCNQ3, plays an important role in limiting network excitability in the neonatal brain. Kv7.2/Kv7.3 dysfunction resulting from KCNQ2 mutations predominantly causes self-limited or benign epilepsy in neonates, but also causes early onset epileptic encephalopathy. Retigabine (RTG), a Kv7.2/ Kv7.3-channel opener, seems to be a rational antiepileptic drug for epilepsies caused by KCNQ2 mutations. We therefore evaluated the effects of RTG on seizures in two strains of knock-in mice harboring different Kcnq2 mutations, in comparison to the effects of phenobarbital (PB), which is the first-line antiepileptic drug for seizures in neonates. The subjects were heterozygous knock-in mice (Kcnq2Y284C/+ and Kcnq2A306T/+) bearing the Y284C or A306T Kcnq2 mutation, respectively, and their wild-type (WT) littermates, at 63–100 days of age. Seizures induced by intraperitoneal injection of kainic acid (KA, 12mg/kg) were recorded using a video-electroencephalography (EEG) monitoring system. Effects of RTG on KA-induced seizures of both strains of knock-in mice were assessed using seizure scores from a modified Racine’s scale and compared with those of PB. The number and total duration of spike bursts on EEG and behaviors monitored by video recording were also used to evaluate the effects of RTG and PB. Both Kcnq2Y284C/+ and Kcnq2A306T/+ mice showed significantly more KA-induced seizures than WT mice. RTG significantly attenuated KA-induced seizure activities in both Kcnq2Y284C/+ and Kcnq2A306T/+ mice, and more markedly than PB. This is the first reported evidence of RTG ameliorating KA-induced seizures in knock-in mice bearing mutations of Kcnq2, with more marked effects than those observed with PB. RTG or other Kv7.2-channel openers may be considered as first-line antiepileptic treatments for epilepsies resulting from KCNQ2 mutations.

Genetics and genotype–phenotype correlations in early onset epileptic encephalopathy with burst suppression

“…For example, ezogabine is an anti-epileptic drug acting on potassium channels and may be beneficial in patients with loss of function KCNQ2 pathogenic variants, though formal studies have yet to be performed. 45, 46 While many variants are considered dominant negative, some may in contrast enhance potassium channel activity. 47, 48 Care must be taken to adequately assess the type and degree of dysfunction, which can be done through emerging international collaborative efforts centered around KCNQ2 such as the Rational Intervention for KCNQ2/3 Epileptic Encephalopathy Project (www.RIKEE.org).…”

Modulation of Kv7 channels and excitability in the brain

“…It was determined that the functional difference in this severe form of single amino acid mutation is derived from not only a reduction of functional expression of Kv7 channels but also loss of localization of Kv7 channels to the AIS [152]. As a consequence of the growing literature on pathologies associated with Kv7 mutations there has been an effort to develop genetically engineered animals to recapitulate and understand the pathologies of the numerous implicated mutations and better understand underlying causes [159,160] as well as the effectiveness of potential therapies [161]. …”

Abnormal γ‐aminobutyric acid neurotransmission in a Kcnq2 model of early onset epilepsy

“…12 To better understand why KCNQ2 mutation-mediated dysfunction of M-channels leads to neuronal hyperexcitability, various groups have introduced epilepsy-associated Kcnq2 variants into mice, which resulted in increased vulnerability to electroconvulsive treatment (maximal electroshock as well as 6-Hz stimulation) 13 and drug-induced seizures. 14,15 Truncation 16 or removal 9,17 of the Kcnq2 gene in mice lowered the seizure threshold in adult heterozygotes, but led to death within hours after birth due to pulmonary malformation in homozygotic knockouts.…”