Evaluation of a New Riluzole‐Based Compound VA945 on Sodium and Potassium Conductances Expressed by SH-SY5Y-Derived Neurons

Riluzole (Rilutek), a derivative of benzothiazole, acts as a neuroprotective agent by inhibiting voltage-dependent sodium (Na+) and delaying rectifier potassium (K+) currents. By doing so, it helps reduce excitotoxicity, a key pathogenetic mechanism in various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although riluzole is a clinically approved treatment for ALS, it is not fully effective, particularly in advanced stages of the disease. In this study, we functionally characterized a newly synthetized riluzole-based compound, VA945, with potentially enhanced neuroprotective effects. By means of SH-SY5Y human neuroblastoma cells differentiated into neurons, we assessed using whole-cell patch-clamp techniques the effects of VA945 on voltage-dependent Na+ and K+ currents at extracellular concentrations of 5, 50, and 100 μM. The compound reduced maximal activation and inactivation of Na+ conductance, as well as maximal activation of K+ conductance, across all tested concentrations. We also observed shifts of the activation and inactivation curves to more hyperpolarized potentials along with changes in the slope factor (k), indicating an altered voltage sensitivity of voltage-dependent K+ and Na+ channels. While the activation kinetics of both channels remained unaffected, and the inactivation kinetics of Na+ were unchanged, we noted a slowdown in the deactivation kinetics of the K+ channels. Altogether, these findings suggest that VA945 exerts multi-target pharmacological effects on neuronal voltage-dependent ion currents critically involved in excitotoxicity and neurodegeneration, across a wide range of concentrations. This warrants further ex vivo and/or in vivo studies to explore its potential as a neuroprotective agent. (Figure presented.).