Simvastatin enhances BK αβ4 channel activity and dose-dependently reduces pilocarpine-induced seizures in mice, effects reversed by BK blocker paxilline.
Simvastatin exerts neuroprotective and anti-seizure effects by directly modulating β4-containing BK channels, providing a molecular basis for repurposing statins in neurological disorders.
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Abstract Background and Purpose Simvastatin has neuroprotective effects in neurological disorders; yet its mechanisms remain incompletely elucidated. Large‐conductance calcium‐activated potassium (BK) channels, containing the brain‐enriched β 4 subunits, are implicated in neurological disorders and represent a potential target for simvastatin. Although simvastatin bidirectionally modulates vascular β 1 subunit‐containing BK channels, its direct effects, calcium dependence and specificity for neuronal β 4‐containing BK channels remain unclear. Experimental Approach Different BK channel plasmids were heterologously expressed in HEK293T cells, and channel currents were recorded using an inside‐out patch clamp configuration. Epilepsy was induced in mice using pilocarpine and assessed through combined Racine scale behavioural analysis and electroencephalographic recordings. Key Results Simvastatin directly modulates BK α channels in a calcium‐dependent manner. Two Ca 2+ ‐binding sites mediate this interaction. Simvastatin potently enhances the activity of BK αβ 4 channels both with and without 1 μM Ca 2+ i . Additionally, simvastatin mitigates pilocarpine‐induced epileptic behaviour in female ICR mice in a dose‐dependent manner, which the BK channel blocker paxilline can reverse. Conclusion and Implications This study identifies BK channel modulation as a novel mechanism underlying simvastatin's neuroprotective effects. β 4‐containing BK channels are a molecular target of simvastatin in vitro, and their activation profile aligns with simvastatin's anti‐seizure effects in vivo. These findings provide a molecular basis for repurposing statins and developing targeted therapies for neurological disorders.
Li et al. (Tue,) reported a other. Simvastatin enhances BK αβ4 channel activity and dose-dependently reduces pilocarpine-induced seizures in mice, effects reversed by BK blocker paxilline.