Electrophysiological evidence of neuronal action potential alterations by a hydroxycinnamic acid derivative at the peripheral level

Year 2025, Volume: 4 Issue: 2, 77 - 83, 31.08.2025

Feyza Alyu Altınok , Abderaouf Boubekka , Ahmed Hasan , Ilhem Dallali , Yusuf Burak , Nilgün Öztürk , Yusuf Ozturk

https://doi.org/10.55971/EJLS.1712839

Abstract

Hydroxycinnamic acid derivatives have emerged as promising agents in pain management due to their multifaceted actions on various processes, including neuronal excitability. In this study, we investigated the electrophysiological effects of ferulic acid, a hydroxycinnamic acid derivative, on primary cultured dorsal root ganglion neurons using the whole-cell patch-clamp technique. Acute application of ferulic acid at a dose of 100 µM to the external solution resulted in a significant hyperpolarization of the resting membrane potential, indicating a stabilization of the neuronal membrane and a reduction in baseline excitability. Furthermore, ferulic acid induced a more negative afterhyperpolarization phase, suggesting enhanced potassium conductance and prolonged refractory periods. Notably, the threshold for action potential initiation became less negative following treatment, demonstrating that a stronger depolarizing stimulus was required to elicit neuronal firing. These changes collectively reflect a decrease in neuronal excitability that extends beyond anti-inflammatory or antioxidant effects, highlighting direct modulation of ion channel dynamics as a key mechanism. The findings provide mechanistic insight into the analgesic potential of ferulic acid by demonstrating its ability to alter action potential parameters and suppress excitability in peripheral sensory neurons. This study supports the therapeutic relevance of hydroxycinnamic acid derivatives in the development of novel analgesics targeting peripheral nociceptive pathways.

Keywords

Action potential , dorsal root ganglion neurons , ferulic acid , patch clamp technique

Ethical Statement

This study was conducted using Sprague-Dawley rats. All procedures involving animals were carried out in full compliance with the European Directive 2010/63/EU on the protection of animals used for scientific purposes. The experimental protocol received approval from the Local Animal Ethics Committee at Anadolu University in Eskisehir, Turkey (Approval No: 2022-11).

Supporting Institution

This study was supported by the Anadolu University Scientific Research Foundation (AUBAP-2203S021, Eskisehir, Türkiye).

Project Number

AUBAP-2203S021

References

• Sapunar D, Kostic S, Banozic A, Puljak L. Dorsal root ganglion–a potential new therapeutic target for neuropathic pain. J Pain Res. 2012;5:31-8. https://doi.org/10.2147/JPR.S26603
• Zhou Y, Zhou ZS, Zhao ZQ. Neomycin blocks capsaicin-evoked responses in rat dorsal root ganglion neurons. Neurosci Lett. 2001;315(1-2):98-102. https://doi.org/10.1016/S0304-3940(01)02356-4
• Dhaliwal J, Dhaliwal N, Akhtar A, Kuhad A, Chopra K. Beneficial effects of ferulic acid alone and in combination with insulin in streptozotocin induced diabetic neuropathy in Sprague Dawley rats. Life Sci. 2020;255:117856. https://doi.org/10.1016/j.lfs.2020.117856
• Kim JK, Park SU. A recent overview on the biological and pharmacological activities of ferulic acid. EXCLI J. 2019;18:132-138. http://dx.doi.org/10.17179/excli2019-1138
• Vashistha B, Sharma A, Jain V. Ameliorative potential of ferulic acid in vincristine-induced painful neuropathy in rats: an evidence of behavioral and biochemical examination. Nutr Neurosci. 2017;20(1):60-70. https://doi.org/10.1179/1476830514Y.0000000165
• Xu Y, Zhang L, Shao T, Ruan L, Wang L, Sun J, Li J, Zhu X, O’Donnell JM, Pan J. Ferulic acid increases pain threshold and ameliorates depression-like behaviors in reserpine-treated mice: behavioral and neurobiological analyses. Metab Brain Dis. 2013;28(4):571-583. https://doi.org/10.1007/s11011-013-9404-4
• Xu Y, Lin D, Yu X, Xie X, Wang L, Lian L, Fei N, Chen J, Zhu N, Wang G, Huang X. The antinociceptive effects of ferulic acid on neuropathic pain: involvement of descending monoaminergic system and opioid receptors. Oncotarget. 2016;7(15):20455-68. https://doi.org/10.18632/oncotarget.7973
• Liu B, Linley JE, Du X, Zhang X, Ooi L, Zhang H, Gamper N. The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+-activated Cl- channels. J Clin Invest. 2010;120(4):1240-1252. https://doi.org/10.1172/jci41084
• Zhang A, Xu C, Liang S, Gao Y, Li G, Wei J, Wan F, Liu S, Lin J. Role of sodium ferulate in the nociceptive sensory facilitation of neuropathic pain injury mediated by P2X3 receptor. Neurochem Int. 2008;53(6-8):278-282. https://doi.org/10.1016/j.neuint.2008.08.008
• Ozcan M, Ayar A. Modulation of action potential and calcium signaling by levetiracetam in rat sensory neurons. J Recept Signal Transduction. 2012;32(3):156-162. https://doi.org/10.3109/10799893.2012.672993
• Anderson M, Zheng Q, Dong X. Investigation of pain mechanisms by calcium imaging approaches. Neurosci Bull. 2018;34(1):194-199. https://doi.org/10.1007/s12264-017-0139-9
• Contardi M, Lenzuni M, Fiorentini F, Summa M, Bertorelli R, Suarato G, Athanassiou A. Hydroxycinnamic acids and derivatives formulations for skin damages and disorders: A review. Pharmaceutics. 2021;13(7):999. https://doi.org/10.3390/pharmaceutics13070999
• Pessoa RT, Santos da Silva LY, Alcântara IS, Silva TM, Silva EDS, da Costa RHS, de Menezes IRA. Antinociceptive potential of Ximenia americana L. bark extract and caffeic acid: Insights into pain modulation pathways. Pharmaceuticals. 2024;17(12):1671. https://doi.org/10.3390/ph17121671
• Altinok FA, Dallali I, Boubekka A, Hasan A, Ozturk Y. Optimized primary dorsal root ganglion cell culture protocol for reliable K+ current patch-clamp recordings. Neurosci Lett. 2025; 844:138038. https://doi.org/10.1016/j.neulet.2024.138038
• Yagi J, Sumino R. Inhibition of a hyperpolarization-activated current by clonidine in rat dorsal root ganglion neurons. J Neurophysiol. 1998;80(3):1094-1104. https://doi.org/10.1152/jn.1998.80.3.1094
• Herzog RI, Cummins TR, Waxman SG. Persistent TTX-resistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons. J Neurophysiol. 2001;86(3):1351-1364. https://doi.org/10.1152/jn.2001.86.3.1351
• Xie RG, Zheng DW, Xing JL, Zhang XJ, Song Y, Xie YB, Kuang F, Dong H, You SW, Xu H, Hu SJ. Blockade of persistent sodium currents contributes to the riluzole-induced inhibition of spontaneous activity and oscillations in injured DRG neurons. PloS one. 2011;6(4):e18681. https://doi.org/10.1371/journal.pone.0018681
• Zheng Q, Fang D, Cai J, Wan Y, Han JS, Xing GG. Enhanced excitability of small dorsal root ganglion neurons in rats with bone cancer pain. Mol Pain. 2012;8:1744-8069. https://doi.org/10.1186/1744-8069-8-24
• Drukarch B, Wilhelmus MM. Thinking about the action potential: the nerve signal as a window to the physical principles guiding neuronal excitability. Front Cell Neurosci. 2023;17:1232020. https://doi.org/10.3389/fncel.2023.1232020