Galangin, a novel Kv7 potassium channel opener, exerts potent antinociceptive effects in multiple chronic pain mouse models.

Abstract

The activation of voltage-gated potassium Kv7/M channels is an attractive therapeutic strategy for chronic pain. Galangin, the principal active component of the medicinal herb Alpinia officinarum Hance, has exhibited analgesic effects in mice. In this study, we investigated the antinociceptive effects of galangin in the treatment of various types of chronic pain and the underlying mechanisms. Using whole-cell recordings of CHO cells expressing Kv7.2/Kv7.3 channels, we showed that galangin enhanced Kv7.2/Kv7.3 currents in a concentration-dependent manner, with an ECvalue of 8.8 ± 1.6 μM, and shifted the voltage-dependent activation curve of the channels toward depolarization. We demonstrated that galangin selectively and potently activated the Kv7.2, Kv7.4, and Kv7.5 channels while reducing the Kv7.1 current and exerting no effect on the Kv7.3 current. Notably, galangin no longer increased the current amplitude and slightly shifted the voltage-dependent activation of the Kv7.2 (E322A) mutant, suggesting that Glu-322 in Kv7.2 is important for galangin activation of the channels. Moreover, we showed that galangin (100 μM) significantly enhanced the M-current and consequently reduced the excitability of DRG neurons in SNI mice. In multiple chronic pain mouse models, the administration of galangin (15 mg/kg, i.p.) significantly increased the threshold for mechanical stimuli and the withdrawal latency to thermal stimuli, which were reversed by the Kv7/M channel blocker XE991. Taken together, the results of this study demonstrated that galangin exerts its antinociceptive effects mainly through the activation of Kv7/M channels, representing a novel approach for treating neuronal excitatory diseases.