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Fenamates Inhibit Human Sodium Channel Nav1.2 and Protect Glutamate-Induced Injury in SH-SY5Y Cells


Voltage-gated sodium channels are crucial mediators of neuronal damage in ischemic and excitotoxicity disease models. Fenamates have been reported to have anti-inflammatory properties following a decrease in prostaglandin synthesis. Several researches showed that fenamates appear to be ion channel modulators and potential neuroprotectants. In this study, the neuroprotective effects of tolfenamic acid, flufenamic acid, and mefenamic acid were tested by glutamate-induced injury in SH-SY5Y cells. Following this, fenamates’ effects were examined on both the expression level and the function of hNav1.1 and hNav1.2, which were closely associated with neuroprotection, using Western blot and patch clamp. Finally, the effect of fenamates on the expression of apoptosis-related proteins in SH-SY5Y cells was examined. The results showed that both flufenamic acid and mefenamic acid exhibited neuroprotective effects against glutamate-induced injury in SH-SY5Y cells. They inhibited peak currents of both hNav1.1 and hNav1.2. However, fenamates exhibited decreased inhibitory effects on hNav1.1 when compared to hNav1.2. Correspondingly, the inhibitory effect of fenamates was found to be consistent with the level of neuroprotective effects in vitro. Fenamates inhibited glutamate-induced apoptosis through the modulation of the Bcl-2/Bax-dependent cell death pathways. Taken together, Nav1.2 might play a part in fenamates’ neuroprotection mechanism.

Graphic Abstract

Nav1.2 and NMDAR might take part in the neuroprotection mechanism of the fenamates. The fenamates inhibited glutamate-induced apoptosis through modulation of the Bcl-2/Bax-dependent cell death pathways.

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Central nervous system


Voltage-gated sodium channel


Nonsteroidal anti-inflammatory drugs


Dorsal root ganglion


Reactive oxygen species


Middle cerebral artery occlusion


Dulbecco's modified Eagle medium


Iscove's modified Dulbecco's medium


Chinese hamster ovary


Fetal bovine serum


American Type Culture Collection


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We gratefully acknowledge the financial support from the Innovation Team Project of the Department of Education of Liaoning Province (LT2015010) and the PhD Start-up Fund of Natural Science Foundation of Liaoning Province (2019-BS-231).

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All authors contributed to the study conception and design. JS, YX, and XK carried out electrophysiology studies. JS carried out MTT assay. JS, YX, and YS carried out Western blot experiments and Annexin V-FITC/PI analysis. YX and ZW conceived and designed the experiments. JS, MZ, and YX wrote this manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yi-Jia Xu or Zhan-You Wang.

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Sun, JF., Zhao, MY., Xu, YJ. et al. Fenamates Inhibit Human Sodium Channel Nav1.2 and Protect Glutamate-Induced Injury in SH-SY5Y Cells. Cell Mol Neurobiol 40, 1405–1416 (2020).

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  • Neuroprotection
  • Fenamates
  • Voltage-gated sodium channel
  • Apoptosis