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

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Abstract

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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Abbreviations

CNS:

Central nervous system

VGSC:

Voltage-gated sodium channel

NSAIDs:

Nonsteroidal anti-inflammatory drugs

DRG:

Dorsal root ganglion

ROS:

Reactive oxygen species

MCAO:

Middle cerebral artery occlusion

DMEM:

Dulbecco's modified Eagle medium

IMDM:

Iscove's modified Dulbecco's medium

CHO:

Chinese hamster ovary

FBS:

Fetal bovine serum

ATCC:

American Type Culture Collection

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Acknowledgements

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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Authors and Affiliations

  1. College of Life and Health Sciences, Northeastern University, Shenyang, 110169, People’s Republic of China

    Jian-Fang Sun & Zhan-You Wang

  2. School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China

    Ming-Yi Zhao, Yi-Jia Xu & Xiao-Hua Kong

  3. Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China

    Yang Su

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  1. Jian-Fang Sun
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  4. Yang Su
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  6. Zhan-You Wang
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Contributions

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.

Corresponding authors

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). https://doi.org/10.1007/s10571-020-00826-1

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