2018 - Fenamates inhibit human sodium channel Nav1.7 and Nav1.8
Port-a-Patch publication in Neuroscience Letters (2018)
Sun, J-F., Xu, Y-J., Kong, X-H., Su, Y., Wang, Z-Y.
Neuroscience Letters (2018) In Press, accepted manuscript.
• Fenamates act as inhibitors of hNav1.7 and hNav1.8.
• Nav1.7 and Nav1.8 might be involved in the analgesic mechanism of the fenamates.
• hNav1.7 might be more important for the analgesic effects of the fenamates than hNav1.8.
• Minor perturbations in fenamates lead to minor changes in the reaction with hNav1.7 and hNav1.8.
Fenamates are N-substituted anthranilic acid derivatives, clinically used as nonsteroidal anti-inflammatory drugs (NSAIDs) in fever, pain and inflammation treatments. Previous studies have shown that they are also modulators of diverse ion channels, exhibiting either activation or inhibitory effects. However, the effects of fenamates on sodium channel subtypes are still unknown. In this study, fenamates, including mefenamic acid, flufenamic acid and tolfenamic acid, were examined by whole-cell patch clamp techniques on the sodium channels hNav1.7 and hNav1.8, which are closely associated with pain. The results showed that the mefenamic acid, flufenamic acid, and tolfenamic acid inhibited the peak currents of hNav1.7 and hNav1.8 in CHO cells stably expressing hNav1.7 and hNav1.8. However, much lighter inhibition effects of hNav1.8 were registered in the experimental system. Furthermore, the mefenamic acid, flufenamic acid and tolfenamic acid significantly affected the inactivation processes of hNav1.7 and hNav1.8 with I-V curves left-shifted to hyperpolarized direction. These data indicate that the inhibition effects of Nav1.7 and Nav1.8 by mefenamic acid, flufenamic acid and tolfenamic acid might contribute to their analgesic activity in addition to their inhibition of cyclooxygenase..These findings provide a basis for further studies in the discovery of other potential targets for NSAIDs.