Fenamates Inhibit Human Sodium Channel Nav1.2 and Protect Glutamate-Induced Injury in SH-SY5Y Cells
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ORIGINAL RESEARCH
Fenamates Inhibit Human Sodium Channel Nav1.2 and Protect Glutamate‑Induced Injury in SH‑SY5Y Cells Jian‑Fang Sun1 · Ming‑Yi Zhao2 · Yi‑Jia Xu2 · Yang Su3 · Xiao‑Hua Kong2 · Zhan‑You Wang1 Received: 27 December 2019 / Accepted: 2 March 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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 glutamateinduced apoptosis through modulation of the Bcl-2/Bax-dependent cell death pathways.
Keywords Neuroprotection · Fenamates · Voltage-gated sodium channel · Apoptosis
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Abbreviations CNS Central nervous system VGSC Voltage-gated sodium channel
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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
Introduction Neurons are known to be susceptible to ischemic injury. Glutamate receptors, which are widely distributed in the central nervous system (CNS), are one of the mechanisms of neuron ischemic susceptibility (Rothman 1984; Simon et al. 1984). They can lead to excitotoxic neuro-degenerative changes when over-activated (Olney 1978). Recent research has focused on voltage-gated sodium channel (VGSC-) inhibitors, which may be able to protect the surviving neurons from f
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