Sun Jian-Fang, Xu Yi-Jia, Kong Xiao-Hua, Su Yang, Wang Zhan-You
College of Life and Health Sciences, Northeastern University, Shenyang, 110169, PR China.
School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
Neurosci Lett. 2019 Mar 23;696:67-73. doi: 10.1016/j.neulet.2018.12.008. Epub 2018 Dec 5.
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.
芬那酸盐是N-取代邻氨基苯甲酸衍生物，临床上用作非甾体抗炎药（NSAIDs）来治疗发热、疼痛和炎症。先前的研究表明，它们也是多种离子通道的调节剂，具有激活或抑制作用。然而，芬那酸盐对钠通道亚型的影响仍不清楚。在本研究中，采用全细胞膜片钳技术，研究了包括甲芬那酸、氟芬那酸和托芬那酸在内的芬那酸盐对与疼痛密切相关的钠通道hNav1.7和hNav1.8的作用。结果表明，甲芬那酸、氟芬那酸和托芬那酸抑制了稳定表达hNav1.7和hNav1.8的CHO细胞中hNav1.7和hNav1.8的峰值电流。然而，在实验系统中，hNav1.8的抑制作用要轻得多。此外，甲芬那酸、氟芬那酸和托芬那酸显著影响hNav1.7和hNav1.8的失活过程，I-V曲线向左移向超极化方向。这些数据表明，甲芬那酸、氟芬那酸和托芬那酸对Nav1.7和Nav1.8的抑制作用，除了抑制环氧化酶外，可能还有助于它们的镇痛活性。这些发现为进一步研究发现NSAIDs的其他潜在靶点提供了基础。
