Polygodial, a drimane sesquiterpenoid dialdehyde purified from Drimys winteri, inhibits voltage-gated sodium channels

Drimys winteri J.R.Forst. & G.Forst, a South American evergreen shrub that is used by the Mapuche people for treatment of several painful conditions, contains polygodial, a lipophilic drimane-type sesquiterpene dialdehyde with known activity at transient receptor potential channel family members including TRPA1 and TRPV1. We sought to assess the activity of polygodial at Na_V1.7 and Na_V1.8, two key isoforms of the voltage-gated sodium channel family involved in nociception. Polygodial was isolated from D. winteri by thin-layer chromatography and analysed structurally by 1 D and 2 D nuclear magnetic resonance (NMR) spectroscopy. Activity at heterologously expressed Na_V1.7 and Na_V1.8 was assessed using automated whole-cell patch-clamp electrophysiology. Here, we show that polygodial inhibits members of the voltage-gated sodium channel family, specifically Na_V1.7 and Na_V1.8, without changing the voltage-dependence of activation or inactivation. Activity of polygodial at voltage-gated sodium channels may contribute to the previously reported antinociceptive properties.