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

Abstract

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 neuro-trophic factor (BDNF) mRNA expression in kindled rats, and kindled rats treated with ISOX. ISOX suppressed sodium current (I Na) showing an IC 50 value of 185 nM in cultured neurons. ISOX significantly slowed the recovery from inactivation (ISOX s = 18.7 ms; Control s = 9.4 ms; p < 0.001). ISOX also enhanced the development of inactivation by shifting the Boltz-mann curve to more hyperpolarized potentials by À11.2 mV (p < 0.05). In naive and electrically kindled cortical neurons, the IC 50 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 < 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. Epilepsy remains a major medical challenge. To date, it is not completely curable and more than 30% of patients worldwide are living with refractory epilepsy. Extracts of plants have been used for many years to treat a variety of neurological disorders. The roots of the plant named Delphinium denud-atum (locally called Jadwar), which is indigenous to the western Himalayas and Kashmir, have been used to treat seizures by local folk medicine practitioners. Chemical

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

“…Voltage-gated sodium channels that play a major role in controlling neuronal excitability, have also demonstrated their importance during epileptogenesis [50,51]. In our study, the sodium channels in the differentiated NG108-15 cells are mainly due to Nav1.7 expression [39].…”

Neuroinflammatory targets and treatments for epilepsy validated in experimental models

“…Furthermore, BDNF has been shown to induce the upregulation of the voltage‐gated potassium channel Kv1.6. This channel has also been shown to be upregulated in a kindling model causing a profound change in the excitability of parvalbumin positive interneurons . To see if MMP inhibition altered expression of BDNF, immunohistochemistry was performed in brain slices from kindled rats treated with DOX.…”

“…This channel has also been shown to be upregulated in a kindling model causing a profound change in the excitability of parvalbumin positive interneurons. 69 To see if MMP inhibition altered expression of BDNF, immunohistochemistry was performed in brain slices from kindled rats treated with DOX. Of interest, BDNF expression was significantly decreased in this group in comparison to saline-treated kindled rats.…”

Immunity, Ion Channels and Epilepsy

“…Molecular studies of epileptogenesis and epilepsy have demonstrated that specific ion channels play an important role in both genetic and acquired forms of epilepsy [ 70 , 71 , 72 ], especially voltage-gated sodium channels [ 73 , 74 , 75 , 76 , 77 ]. The ionic mechanisms underlying burst-firing behavior in neurons are not fully understood, although sodium channels have been found to be significantly involved [ 72 , 78 ].…”