Skip to main content

Fisetin decreases the duration of ictal-like discharges in mouse hippocampal slices

Abstract

There is an increasing interest in the biological and therapeutic effects of fisetin, a natural phenolic compound. Fisetin has affinity on some neuronal targets and may have the potential to modulate neuronal activity. In this study the effects of acute application of fisetin on synchronized events were evaluated electro-physiologically. Besides, interaction of fisetin with closely related channels were investigated in silico. Acute horizontal hippocampal slices were obtained from 32- to 36-day-old C57BL/6 mice. Extracellular field potentials were recorded from CA3 region of the hippocampus. Bath application of 4 aminopyridine (4AP, 100 µM) initiated ictal- and interictal-like synchronized epileptiform discharges in the brain slices. Fifty micromolar fisetin was applied to the recording chamber during the epileptiform activity. The duration and frequencies of both ictal-like and interictal-like activities were calculated from the electrophysiological records. Molecular docking was performed to reveal interaction of fisetin on GABA-A, NMDA, AMPA receptors, and HCN2 channel, which are neuronal structures directly involved in recorded activity. Although fisetin does not affect basal neuronal activity in brain slice, it reduced the duration of ictal-like discharges significantly. Molecular docking results indicated that fisetin has no effect on GABA-A, NMDA, and AMPA receptors. However, fisetin binds to the (5JON) HCN2 channel strongly with the binding energy of −7.66 kcal/mol. Reduction on the duration of 4AP-induced ictal-like discharges can be explained as HCN channels can cause an inhibitory effect via enhancing M-type K + channels which increase K outward currents.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Milligan, T.A.: Epilepsy: a clinical overview. Am. J. Med. (2021). https://doi.org/10.1016/j.amjmed.2021.01.038

    Article  Google Scholar 

  2. Sucher, N.J., Carles, M.C.: A pharmacological basis of herbal medicines for epilepsy. Epilepsy Behav. (2015). https://doi.org/10.1016/j.yebeh.2015.05.012

    Article  Google Scholar 

  3. Ravula, A.R., Teegala, S.B., Kalakotla, S., Pasangulapati, J.P., Perumal, V., Boyina, H.K.: Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: an updated review. Eur. J. Pharmacol. (2021). https://doi.org/10.1016/j.ejphar.2021.174492

    Article  Google Scholar 

  4. Grynkiewicz, G., Demchuk, O.M.: New perspectives for fisetin. Front. Chem. (2019). https://doi.org/10.3389/fchem.2019.00697

    Article  Google Scholar 

  5. Maher, P.: Modulation of the neuroprotective and anti-inflammatory activities of the flavonol fisetin by the transition metals iron and copper. Antioxidants (2020). https://doi.org/10.3390/antiox9111113

    Article  Google Scholar 

  6. Imran, M., Saeed, F., Gilani, S.A., Shariati, M.A., Imran, A., Afzaal, M., Atif, M., Tufail, T., Anjum, F.M.: Fisetin: an anticancer perspective. Food Sci. Nutr. (2020). https://doi.org/10.1002/fsn3.1872

    Article  Google Scholar 

  7. Krasieva, T.B., Ehren, J., O’Sullivan, T., Tromberg, B.J., Maher, P.: Cell and brain tissue imaging of the flavonoid fisetin using label-free two-photon microscopy. Neurochem. Int. (2015). https://doi.org/10.1016/j.neuint.2015.08.003

    Article  Google Scholar 

  8. He, W.B., Abe, K., Akaishi, T.: Oral administration of fisetin promotes the induction of hippocampal long-term potentiation in vivo. J. Pharmacol. Sci. (2018). https://doi.org/10.1016/j.jphs.2017.12.008

    Article  Google Scholar 

  9. Cordaro, M., D’Amico, R., Fusco, R., Peritore, A.F., Genovese, T., Interdonato, L., Franco, G., Arangia, A., Gugliandola, E., Crupi, R., Siracusa, R., Di Paola, R., Cuzzocrea, S., Impellizzeri, D.: Discovering the effects of fisetin on nf-κb/nlrp-3/nrf-2 molecular pathways in a mouse model of vascular dementia induced by repeated bilateral carotid occlusion. Biomedicines (2022). https://doi.org/10.3390/biomedicines10061448

    Article  Google Scholar 

  10. Zhen, L., Zhu, J., Zhao, X., Huang, W., An, Y., Li, S., Du, X., Lin, M., Wang, Q., Xu, Y., Pan, J.: The antidepressant-like effect of fisetin involves the serotonergic and noradrenergic system. Behav. Brain Res. (2012). https://doi.org/10.1016/j.bbr.2011.12.017

    Article  Google Scholar 

  11. Raygude, K.S., Kandhare, A.D., Ghosh, P., Bodhankar, S.L.: Anticonvulsant effect of fisetin by modulation of endogenous biomarkers. Biomed. Prev. Nutr. (2012). https://doi.org/10.1016/j.bionut.2012.04.005

    Article  Google Scholar 

  12. Ramírez, D., Zúñiga, R., Concha, G., Zúñiga, L.: HCN channels: new therapeutic targets for pain treatment. Molecules (2018). https://doi.org/10.3390/molecules23092094

    Article  Google Scholar 

  13. Rivolta, I., Binda, A., Masi, A., DiFrancesco, J.C.: Cardiac and neuronal HCN channelopathies. Pflügers Arch. Eur. J. Physiol. (2020). https://doi.org/10.1007/s00424-020-02384-3

    Article  Google Scholar 

  14. DiFrancesco, J.C., Castellotti, B., Milanesi, R., Ragona, F., Freri, E., Canafoglia, L., Franceschetti, S., Ferrarese, C., Magri, S., Taroni, F., Costa, C., Labate, A., Gambardella, A., Solazzi, R., Binda, A., Rivolta, I., Di Gennaro, G., Casciato, S., Gellera, C.: HCN ion channels and accessory proteins in epilepsy: genetic analysis of a large cohort of patients and review of the literature. Epilepsy Res. (2019). https://doi.org/10.1016/j.eplepsyres.2019.04.004

    Article  Google Scholar 

  15. Carlson, A.E., Rosenbaum, J.C., Brelidze, T.I., Klevit, R.E., Zagotta, W.N.: Flavonoid regulation of HCN2 channels. J. Biol. Chem. (2013). https://doi.org/10.1074/jbc.M113.501759

    Article  Google Scholar 

  16. Sharifi-Rad, J., Quispe, C., Herrera-Bravo, J., Martorell, M., Sharopov, F., Tumer, T.B. Kurt, B., Lankatillake, C., docea, A.O., Moreira, A.C., Dias, D.A., Mahomoodally, M.F., Lobine, D., Cru-Martins, N., Kumar, M., Calina, D.: A pharmacological perspective on plant-derived bioactive molecules for epilepsy. Neurochem. Res. (2021). https://doi.org/10.1007/s11064-021-03376-0

  17. Ozturk, H., Yorulmaz, N., Durgun, M., Basoglu, H.: In silico investigation of Alliin as potential activator for AMPA receptor. Biomed. Phys. Eng. Expr. (2021). https://doi.org/10.1088/2057-1976/ac351c

    Article  Google Scholar 

  18. Aydin-Abidin, S., Abidin, İ: 7,8-Dihydroxyflavone potentiates ongoing epileptiform activity in mice brain slices. Neurosci. Lett. (2019). https://doi.org/10.1016/j.neulet.2019.03.013

    Article  Google Scholar 

  19. Abidin, İ, Aydin-Abidin, S., Mittmann, T.: Neuronal excitability and spontaneous synaptic transmission in the entorhinal cortex of BDNF heterozygous mice. Neurosci. Lett. (2019). https://doi.org/10.1016/j.neulet.2018.10.019

    Article  Google Scholar 

  20. Basoglu, H., Ozturk, H., Keser, H., Aydin-Abidin, S., Abidin, I.: L-Theanine reduces epileptiform activity in brain slices. Akd. Tıp D. (2022). https://doi.org/10.53394/akd.1057342

  21. D’Arcangelo, G., Panuccio, G., Tancredi, V., Avoli, M.: Repetitive low-frequency stimulation reduces epileptiform synchronization in limbic neuronal networks. Neurobiol. Dis. (2005). https://doi.org/10.1016/j.nbd.2004.11.012

    Article  Google Scholar 

  22. Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., Olson, A.J.: AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem. (2009). https://doi.org/10.1002/jcc.21256

    Article  Google Scholar 

  23. Hanwell, M.D., Curtis, D.E., Lonie, D.C., Vandermeersch, T., Zurek, E., Hutchison, G.R.: Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform. (2012). https://doi.org/10.1186/1758-2946-4-17

    Article  Google Scholar 

  24. Bechthold, E., Schreiber, J.A., Lehmkuhl, K., Frehland, B., Schepmann, D., Bernal, F.A., Daniliuc, C., Alvarez, I., Garcia, C.V., Schmidt, T.J., Seebohm, G., Wünsch, B.: Ifenprodil stereoisomers: synthesis, absolute configuration, and correlation with biological activity. J. Med. Chem. (2021). https://doi.org/10.1021/acs.jmedchem.0c01912

    Article  Google Scholar 

  25. Rogawski, M.A., Hanada, T.: Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol. Scand. Suppl. (2013). https://doi.org/10.1111/ane.12100

    Article  Google Scholar 

  26. Gong, P., Hong, H., Perkins, E.J.: Ionotropic GABA receptor antagonism-induced adverse outcome pathways for potential neurotoxicity biomarkers. Biomark. Med. (2015). https://doi.org/10.2217/bmm.15.58

    Article  Google Scholar 

  27. Severina, H.I., Georgiyants, V.A., Kovalenko, S.M., Avdeeva, N.V., Yarcev, A.I., Prohoda, S.N.: Molecular docking studies of N-substituted 4-methoxy-6-oxo-1-aryl-pyridazine-3-carboxamide derivatives as potential modulators of glutamate receptors. Res. Results Pharmacol. (2020). https://doi.org/10.3897/rrpharmacology.6.52026

    Article  Google Scholar 

  28. Gallagher, M.J., Huang, H., Pritchett, D.B., Lynch, D.R.: Interactions between ifenprodil and the NR2B subunit of the N-methyl-D-aspartate receptor. J. Biol. Chem. (1996). https://doi.org/10.1074/jbc.271.16.9603

    Article  Google Scholar 

  29. Di Bonaventura, C., Labate, A., Maschio, M., Meletti, S., Russo, E.: AMPA receptors and perampanel behind selected epilepsies: current evidence and future perspectives. Expert Opin. Pharmacother. (2017). https://doi.org/10.1080/14656566.2017.1392509

    Article  Google Scholar 

  30. Sigel, E., Steinmann, M.E.: Structure, function, and modulation of GABA(A) receptors. J. Biol. Chem. (2012). https://doi.org/10.1074/jbc.R112.386664

    Article  Google Scholar 

  31. Zhu, S., Noviello, C.M., Teng, J., Walsh, R.M., Jr., Kim, J.J., Hibbs, R.E.: Structure of a human synaptic GABA(A) receptor. Nature (2018). https://doi.org/10.1038/s41586-018-0255-3

    Article  Google Scholar 

  32. Robinson, R.B., Siegelbaum, S.A.: Hyperpolarization-activated cation currents: from molecules to physiological function. Annu. Rev. Physiol. (2003). https://doi.org/10.1146/annurev.physiol.65.092101.142734

    Article  Google Scholar 

  33. Craven, K.B., Zagotta, W.N.: CNG and HCN channels: two peas, one pod. Annu. Rev. Physiol. (2006). https://doi.org/10.1146/annurev.physiol.68.040104.134728

    Article  Google Scholar 

  34. Goldschen-Ohm, M.P., Klenchin, V.A., White, D.S., Cowgill, J.B., Cui, Q., Goldsmith, R.H., Chanda, B.: Structure and dynamics underlying elementary ligand binding events in human pacemaking channels. Struct. Biol. Mol. Biophys. (2016). https://doi.org/10.7554/eLife.20797

    Article  Google Scholar 

  35. Meng, X.Y., Zhang, H.X., Mezei, M., Cui, M.: Molecular docking: a powerful approach for structure-based drug discovery. Curr. Comput. Aided Drug Des. (2011). https://doi.org/10.2174/157340911795677602

    Article  Google Scholar 

  36. Isika, D., Çeşme, M., Osonga, F.J., Sadik, O.A.: Novel quercetin and apigenin-acetamide derivatives: design, synthesis, characterization, biological evaluation and molecular docking studies. RSC Adv. (2020). https://doi.org/10.1039/D0RA04559D

    Article  Google Scholar 

  37. Bissantz, C., Folkers, G., Rognan, D.: Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. J. Med. Chem. (2000). https://doi.org/10.1021/jm001044l

  38. Kase, D., Imoto, K.: The role of HCN Channels on membrane excitability in the nervous system. J. Signal Transduct. (2012). https://doi.org/10.1155/2012/619747

    Article  Google Scholar 

  39. George, M.S., Abbott, L.F., Siegelbaum, S.A.: HCN hyperpolarization-activated cation channels inhibit EPSPs by interactions with M-type K(+) channels. Nat. Neurosci. (2009). https://doi.org/10.1038/nn.2307

    Article  Google Scholar 

  40. Lin, W., Qin, J., Ni, G., Li, Y., Xie, H., Yu, J., Li, H., Sui, L., Guo, Q., Fang, Z., Zhou, L.: Downregulation of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in the hippocampus of patients with medial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS). Hippocampus (2020). https://doi.org/10.1002/hipo.23219

    Article  Google Scholar 

  41. Das, J., Singh, R., Sharma, D.: Antiepileptic effect of fisetin in iron-induced experimental model of traumatic epilepsy in rats in the light of electrophysiological, biochemical, and behavioral observations. Nutr. Neurosci. (2017). https://doi.org/10.1080/1028415x.2016.1183342

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Harun Basoglu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 592 KB)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ozturk, H., Basoglu, H., Yorulmaz, N. et al. Fisetin decreases the duration of ictal-like discharges in mouse hippocampal slices. J Biol Phys 48, 355–368 (2022). https://doi.org/10.1007/s10867-022-09612-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10867-022-09612-0

Keywords

  • Fisetin
  • 4AP
  • HCN channels
  • Molecular docking
  • Brain slice