A novel anticonvulsant modulates voltage-gated sodium channel inactivation and prevents kindling-induced seizures

作者：Ashraf Muhammad N; Gavrilovici Cezar; Ali Shah Syed U; Shaheen Farzana; Choudhary Muhammad I; Rahman Atta ur; Fahnestock Margaret; Simjee Shabana U; Poulter Michael O^*

来源：Journal of Neurochemistry, 2013, 126(5): 651-661.

DOI：10.1111/jnc.12352

• brain-derived neurotrophic factor
• electrophysiology
• Isoxylitones [E
• Z]
• steady-state inactivation

Here, we explore the mechanism of action of isoxylitone (ISOX), a molecule discovered in the plant Delphinium denudatum, which has been shown to have anticonvulsant properties. Patch-clamp electrophysiology assayed the activity of ISOX on voltage-gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy (kindling model). Quantitative transcription polymerase chain reaction (qRT-PCR) (QPCR) assessed brain-derived neurotrophic factor (BDNF) mRNA expression in kindled rats, and kindled rats treated with ISOX. ISOX suppressed sodium current (I-Na) showing an IC50 value of 185nM in cultured neurons. ISOX significantly slowed the recovery from inactivation (ISOX =18.7ms; Control =9.4ms; p%26lt;0.001). ISOX also enhanced the development of inactivation by shifting the Boltzmann curve to more hyperpolarized potentials by -11.2mV (p%26lt;0.05). In naive and electrically kindled cortical neurons, the IC50 for sodium current block was identical to that found in cultured neurons. ISOX prevented kindled stage 5 seizures and decreased the enhanced BDNF mRNA expression that is normally associated with kindling (p%26lt;0.05). Overall, our data show that ISOX is a potent inhibitor of VGSCs that stabilizes steady-state inactivation while slowing recovery and enhancing inactivation development. Like many other sodium channel blocker anti-epileptic drugs, the suppression of BDNF mRNA expression that usually occurs with kindling is likely a secondary outcome that nevertheless would suppress epileptogenesis. These data show a new class of anti-seizure compound that inhibits sodium channel function and prevents the development of epileptic seizures.

• 出版日期2013-9