Osthol is a Use-Dependent Blocker of Voltage-Gated Na⁺ Channels in Mouse Neuroblastoma N2A Cells

Abstract

Osthol, a Chinese herbal compound, has been shown to possess vasorelaxant and neuroprotective properties. Not much is known about the effects of osthol on ionic channels, activities of which are implicated in vasorelaxation and neuroprotection. In this work we report that osthol could inhibit voltage-gated Na⁺ currents with state-dependence in mouse neuroblastoma N2A cells (IC₅₀ = 12.3 µM and 31.5 µM at holding potentials of − 70 mV and − 100 mV, respectively). Current blockade was equally effective in both extracellular and intracellular application of osthol. Osthol (18 µM) did not significantly affect the kinetics and voltage-dependence of Na⁺ channel activation, but left-shifted the steady-state inactivation curve (V_1/2 = − 60.5 mV and − 78.7 mV in the absence and presence of osthol, respectively). Osthol also mildly but significantly retarded channel recovery from inactivation (recovery time constant = 19.9 ms and 35.6 ms in the absence and presence of osthol, respectively). In addition, osthol blocked Na⁺ currents in a frequency-dependent fashion: blockades of 17 %, 34 % and 49 % when currents were triggered at 0.33 Hz, 1 Hz and 3.33 Hz, respectively. Taken together, our results therefore suggest that osthol blocked voltage-gated Na⁺ channels intracellularly with state- and frequency-dependence.

Key words

osthol - voltage‐gated Na⁺ channels - blockade - use‐dependence - state‐dependence - N2A cells

References

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1 These authors contributed equally to this work.