Fluvastatin, an HMG-CoA reductase inhibitor, exerts protective effect against NMDA-induced seizure by increasing the seizure threshold and modulating membrane excitability in embryonic rat cortical neuron

Ya-Jean Wang; Eric Hwang; Hwei-Hisen Chen; Ming-Huan Chan; Che-Jui Yeh; You-Xuan Liu; Chieh-Min Huang

doi:10.1016/j.brainres.2024.149403

Fluvastatin, an HMG-CoA reductase inhibitor, exerts protective effect against NMDA-induced seizure by increasing the seizure threshold and modulating membrane excitability in embryonic rat cortical neuron

Brain Res. 2024 Dec 16:149403. doi: 10.1016/j.brainres.2024.149403. Online ahead of print.

Authors

Ya-Jean Wang¹, Eric Hwang², Hwei-Hisen Chen³, Ming-Huan Chan⁴, Che-Jui Yeh⁵, You-Xuan Liu⁵, Chieh-Min Huang⁶

Affiliations

¹ Department of Senior Services Industry Management, Minghsin University of Science and Technology, Hsinchu, Taiwan. Electronic address: yawang@must.edu.tw.
² Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan; Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
³ Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan; Institute of Neuroscience, National Chengchi University, Taipei, Taiwan. Electronic address: hwei@nhri.org.tw.
⁴ Institute of Neuroscience, National Chengchi University, Taipei, Taiwan. Electronic address: minghuan@nccu.edu.tw.
⁵ Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
⁶ Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.

PMID: 39694167
DOI: 10.1016/j.brainres.2024.149403

Abstract

Background: Epilepsy affects nearly 50 million people worldwide. Previous studies have indicated the neuroprotective effects of statin on several neuropathological conditions. However, it is very much unknown whether fluvastatin was able to alter the seizure types related to neuronal excitability and progression mediated by NMDA receptor activation, and the mechanisms involved in these actions are not completely understood so far. Our study evaluated the effects of fluvastatin on the NMDA-induced seizure, BK_Ca channels activity, NMDA receptor activation opens BK_Ca current, sodium channel current, NMDA receptor-mediated current, and hyperexcitable neuronal activity associated with activation of NMDA receptor.

Methods: The effects of fluvastatin on seizure thresholds induced by NMDA were monitored in mice. The cell-attached and whole-cell patch-clamp recordings were applied to evaluate the ionic currents and action potentials of rCN or SHSY5Y neuroblastoma cells.

Results: The results of our study have demonstrated that fluvastatin did increase the NMDA-induced seizure threshold and suppressed the frequency of action potentials induced by NMDA. Notably, our findings provide the evidence that fluvastatin exhibits inhibitory effects on NMDA receptor-mediated current, BK_Ca channels currents, NMDA receptor activation opens BK_Ca current, and sodium channel currents in rCN and SHSY5Y neuroblastoma cells.

Conclusion: Our findings suggested that fluvastatin may protect against seizure types related to neuronal excitability and NMDA receptor activation by inhibiting NMDA-mediated action potentials, NMDA receptor-mediated currents, BK_Ca channels, and sodium channels.

Keywords: BK(Ca) channel; Fluvastatin; NMDA receptor; NMDA-induced seizure; NMDAR activation opens BK(Ca) current; Sodium channel.