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Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy
Stephanie L Vanhoof-Villalba1, Nicole M Gautier1, Vikas Mishra1
1Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Objectives:
Antiseizure drugs are the leading therapeutic choice for treatment of epilepsy, but their efficacy is limited by pharmacoresistance and the occurrence of unwanted side effects. Here, we examined the therapeutic efficacy of KCNQ channel activation by retigabine in preventing seizures and neurocardiac dysfunction in 2 potassium channelopathy mouse models of epilepsy with differing severity that have been associated with increased risk of sudden unexpected death in epilepsy (SUDEP): the Kcna1-/- model of severe epilepsy and the Kcnq1A340E/A340E model of mild epilepsy.
Methods:
A combination of behavioral, seizure threshold, electrophysiologic, and gene expression analyses was used to determine the effects of KCNQ activation in mice.
Results:
Behaviorally, Kcna1-/- mice exhibited unexpected hyperexcitability instead of the expected sedative-like response. In flurothyl-induced seizure tests, KCNQ activation decreased seizure latency by ≥50% in Kcnq1 strain mice but had no effect in the Kcna1 strain, suggesting the influence of genetic background. However, in simultaneous electroencephalography and electrocardiography recordings, KCNQ activation significantly reduced spontaneous seizure frequency in Kcna1-/- mice by ~60%. In Kcnq1A340E/A340E mice, KCNQ activation produced adverse cardiac effects including profound bradycardia and abnormal increases in heart rate variability and atrioventricular conduction blocks. Analyses of Kcnq2 and Kcnq3 mRNA levels revealed significantly elevated Kcnq2 expression in Kcna1-/- brains, suggesting that drug target alterations may contribute to the altered drug responses.
Significance:
This study shows that treatment strategies in channelopathy may have unexpected outcomes and that effective rebalancing of channel defects requires improved understanding of channel interactions at the circuit and tissue levels. The efficacy of KCNQ channel activation and manifestation of adverse effects were greatly affected by genetic background, potentially limiting KCNQ modulation as a way to prevent neurocardiac dysfunction in epilepsy and thereby SUDEP risk. Our data also uncover a potential role for KCNQ2-5 channels in autonomic control of chronotropy.
Insights
Retigabine
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Epilepsy treatment relies on antiseizure drugs, but pharmacoresistance and side effects limit efficacy.
- Sudden unexpected death in epilepsy (SUDEP) is a risk associated with certain epilepsy types.
- Potassium channelopathies are linked to epilepsy and SUDEP, making ion channels a therapeutic target.
Purpose of the Study:
- To evaluate KCNQ channel activation by retigabine for treating seizures and neurocardiac dysfunction.
- To investigate retigabine's efficacy in two mouse models of epilepsy with varying severity (Kcna1-/- and Kcnq1A340E/A340E).
Main Methods:
- Utilized behavioral analysis, seizure threshold tests, and electrophysiologic recordings (EEG/ECG).
- Performed gene expression analysis (Kcnq2, Kcnq3 mRNA levels).
- Assessed effects in Kcna1-/- (severe epilepsy) and Kcnq1A340E/A340E (mild epilepsy) mouse models.
Main Results:
- Retigabine unexpectedly increased hyperexcitability in Kcna1-/- mice behaviorally.
- KCNQ activation reduced seizure latency in Kcnq1A340E/A340E mice but not Kcna1-/- mice.
- Retigabine significantly decreased seizure frequency in Kcna1-/- mice (~60%) but caused cardiac issues (bradycardia, conduction blocks) in Kcnq1A340E/A340E mice.
- Elevated Kcnq2 expression in Kcna1-/- brains suggests altered drug target interactions.
Conclusions:
- KCNQ channel activation efficacy and side effects are highly dependent on genetic background.
- Unexpected outcomes highlight the need for understanding channel interactions in epilepsy treatment.
- KCNQ modulation may be limited for preventing neurocardiac dysfunction and SUDEP due to genetic variability and potential adverse cardiac effects.
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