[5-Hidroksi-7-(Pentiloksi)-2-Fenil-4h-Kromen-4-One] molekülünün In Silico Özelliklerinin ve Beyin Dilimlerinde In-Vitro Epileptiform Aktivasyon Üzerine Etkilerinin İncelenmesi

Year 2023, Volume: 6 Issue: 3, 352 - 360, 21.10.2023

Harun Başoğlu , Hilal Öztürk , Nuri Yorulmaz , Selcen Abidin , İsmail Abidin

https://doi.org/10.53446/actamednicomedia.1330884

Cited By: 1

Abstract

Amaç: Epilepsi tam tedavisi olmayan bir hastalıktır ve yeni ilaç adaylarının araştırılmasını gerektirir. 5-hidroksi-7-(pentiloksi)-2-fenil-4h-kromen-4-one (5H7P4C4O) molekülü ticari olarak mevcuttur, ancak çözünürlüğü, spektroskopik özellikleri ve biyolojik aktivitesi bilinmemektedir. Bu makale, epilepsi tedavisi için 5H7P4C4O adlı bir molekülün ve bunun merkezi sinir sistemindeki (MSS) potansiyel biyolojik etkilerinin araştırılmasına odaklanmaktadır.
Yöntem: İlk olarak 5H7P4C4O'nun çözünürlüğü ve spektroskopik özellikleri belirlendi. Fizikokimyasal, farmakokinetik ve ilaca benzerlik özellikleri ADME programı ile in silico olarak değerlendirildi. Ayrıca molekülün nörolojik aktivite üzerindeki potansiyeline odaklanılarak, 5H7P4C4O molekülünün NMDA, AMPA ve GABA-A reseptörleri üzerindeki etkileşim potansiyelleri moleküler yerleştirme yöntemiyle incelenmiştir. Bağlanma enerjileri, NMDA ve GABA-A reseptörleri için potansiyel afinite gösterdi. Daha sonra 5H7P4C4O molekülünün akut etkisi, 30-35 günlük C57BL/6 farelerinin beyin kesitlerinde hipokampusun CA3 bölgesinde elektrofizyolojik olarak incelendi. Epileptiform aktivite, Mg+2 içermeyen ortamda veya 4-aminopiridin (4AP, 100 uM) ile indüklendi.
Bulgular: 5H7P4C4O, tek başına uygulandığında 5, 10 ve 20 μM dozlarda hiçbir uyarıcı etki göstermedi. Bununla birlikte, Mg+2 içermeyen modelde iktal sinyalleri söndürdü ve 0-47 Hz frekans aralığındaki sinyallerin toplam gücü üzerinde dikkate değer bir modülatör etki gösterdi.
Sonuç: Elde edilen sonuçlara göre 5H7P4C4O'nun nöronal stimülasyon üzerinde modülatör etki göstermektedir. Bu etkiyi sadece Mg+2 içermeyen modelde göstermesi NMDA reseptörleri üzerinden etkinlik gösterdiğini düşündürmektedir. Ayrıca, güç sinyallerini belirli bir frekans aralığında toplama yeteneği, bilişsel ve/veya diğer beyin işlevlerinde potansiyel etkilerinin olduğunu gösterir.

Keywords

Epilepsi, Beyin Kesitleri, Mg içermeyen, 4AP, Elektrofizyoloji

Investigation of In Silico Properties of [5-Hydroxy-7-(Pentyloxy)-2-Phenyl-4h-Chromen-4-One] molecule and its Effects on In-Vitro Epileptiform Activation in Brain Slices

Abstract

Objective: Epilepsy is an incurable disorder, necessitating research into new drug candidates. The molecule 5-hydroxy-7-(pentyloxy)-2-phenyl-4h-chromen-4-one (5H7P4C4O) is available commercially, but its solubility, spectroscopic properties, and biological activity are unknown. This article focuses on the investigation of a molecule called 5H7P4C4O and its potential biological effects in the central nervous system (CNS) for the treatment of epilepsy.
Methods: Initially, the solubility and spectroscopic properties of 5H7P4C4O were determined. Physicochemical, pharmacokinetic and drug-likeness properties were evaluated in silico with the ADME program. Besides, focusing on the potential of the molecule on the neurological activity, interaction potentials of 5H7P4C4O molecule on NMDA, AMPA and GABA-A receptors was investigated by molecular docking method. Binding energies indicated potential affinity for NMDA and GABA-A receptors. Next, the acute effect of the 5H7P4C4O molecule was electrophysiologically examined in the CA3 region of the hippocampus in brain slices of 30-35 days old C57BL/6 mice. Epileptiform activity was induced in Mg+2-free medium or with 4-aminopyridine (4AP, 100 μM).
Results: When applied alone, 5H7P4C4O exhibited no stimulating effect at doses of 5, 10, and 20 μM. However, it extinguished ictal signals and demonstrated a remarkable modulatory effect on the total power of signals within the 0-47 Hz frequency range in Mg+2-free model.
Conclusion: Based on the results obtained, it was concluded that the 5H7P4C4O indicates modulator effect on neuronal stimulation. Showing this effect only in the Mg+2-free model suggests that it has activity on NMDA receptors. Additionally, its ability to gather power signals within a specific frequency range suggest potential effectiveness in cognitive and/or other brain functions.

Keywords

Epilepsy, Brain slice, Mg-free, 4AP, Electrophysiology

References

• Sharifi-Rad J, Quispe C, Herrera-Bravo J, et al. A Pharmacological Perspective on Plant-derived Bioactive Molecules for Epilepsy. Neurochemical research 2021;46(9):2205-2225, doi:10.1007/s11064-021-03376-0
• Ozturk H, Basoglu H, Yorulmaz N, Aydin-Abidin S, Abidin I. Fisetin decreases the duration of ictal-like discharges in mouse hippocampal slices. Journal of Biological Physics 2022;48(3):355-368, doi:10.1007/s10867-022-09612-0
• Ozturk H, Yorulmaz N, Durgun M, Basoglu H. In silicoinvestigation of Alliin as potential activator for AMPA receptor. Biomedical Physics & Engineering Express. 2021;8(1), doi:10.1088/2057-1976/ac351c
• Hanada T. Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors. Biomolecules 2020;10(3):464
• Hansen KB, Yi F. Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol. 2018;150(8): 1081-1105, doi:10.1085/jgp.201812032
• Blanke ML, VanDongen AMJ. Frontiers in Neuroscience Activation Mechanisms of the NMDA Receptor. In: Biology of the NMDA Receptor. (Van Dongen AM. ed.) CRC Press/Taylor & Francis Copyright © 2009, Taylor & Francis Group, LLC.: Boca Raton (FL); 2009.
• Anderson WW, Anderson WW, Lewis DV, et al. Magnesium-free medium activates seizure-like events in the rat hippocampal slice. Brain research 1986;398(1):215-219, doi:https://doi.org/10.1016/0006-8993(86)91274-6
• Treiman DM. GABAergic mechanisms in epilepsy. Epilepsia 2001;42 Suppl 3(8-12, doi:10.1046/j.1528-1157.2001.042 suppl.3008.x
• Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017;7(1):42717, doi:10.1038/srep42717
• Pinzi L, Rastelli G. Molecular Docking: Shifting Paradigms in Drug Discovery. Int J Mol Sci. 2019;20(18), doi:10.3390/ ijms20184331
• Bertram EH. Temporal lobe epilepsy: Where do the seizures really begin? Epilepsy & Behavior 2009;14(1, Supplement 1):32-37, doi:https://doi.org/10.1016/j.yebeh.2008.09.017
• Abidin İ, Aydin-Abidin S, Mittmann T. Neuronal excitability and spontaneous synaptic transmission in the entorhinal cortex of BDNF heterozygous mice. Neuroscience letters 2019;690(69-75, doi:10.1016/j.neulet.2018.10.019
• Basoglu H OH, Keser H, Aydin-Abidin S, Abidin I. L-Theanine Reduces Epileptiform Activity In Brain Slices. Akdeniz Tıp Dergisi 2022;8(2):121-127, doi:https://doi.org/10.53394/ akd.1057342
• Wang X, He X, Li T, et al. Anti-epileptic effect of ifenprodil on neocortical pyramidal neurons in patients with malformations of cortical development. Experimental and therapeutic medicine 2017;14(6):5757-5766, doi:10.3892/ etm.2017.5311
• Aydin-Abidin S, Abidin İ. 7,8-Dihydroxyflavone potentiates ongoing epileptiform activity in mice brain slices. Neuroscience letters 2019;703(25-31, doi:10.1016/j.neulet. 2019.03.013
• Gorlewicz A, Pijet B, Orlova K, et al. Epileptiform GluN2B-driven excitation in hippocampus as a therapeutic target against temporal lobe epilepsy. Experimental neurology 2022;354(114087, doi:10.1016/j.expneurol.2022.114087
• Masiulis S, Desai R, Uchański T, et al. GABA(A) receptor signalling mechanisms revealed by structural pharmacology. Nature 2019;565(7740):454-459, doi:10.1038/s41586-018-0832-5
• Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews 2001;46(1-3):3-26, doi:10.1016/s0169-409x(00)00129-0
• Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. Journal of combinatorial chemistry 1999;1(1):55-68, doi:10.1021/cc9800071
• Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45(12):2615-23, doi:10.1021/jm020017n
• Egan WJ, Merz KM, Jr., Baldwin JJ. Prediction of drug absorption using multivariate statistics. J Med Chem. 2000;43(21):3867-77, doi:10.1021/jm000292e
• Muegge I, Heald SL, Brittelli D. Simple selection criteria for drug-like chemical matter. J Med Chem. 2001;44(12):1841-6, doi:10.1021/jm015507e
• Martin YC. A bioavailability score. J Med Chem 2005;48(9):3164-70, doi:10.1021/jm0492002
• Potts RO, Guy RH. Predicting skin permeability. Pharmaceutical research 1992;9(5):663-9, doi:10.1023/ a:1015810312465
• Delaney JS. ESOL: estimating aqueous solubility directly from molecular structure. Journal of chemical information and computer sciences 2004;44(3):1000-5, doi:10.1021/ ci034243x
• Ali J, Camilleri P, Brown MB, et al. In Silico Prediction of Aqueous Solubility Using Simple QSPR Models: The Importance of Phenol and Phenol-like Moieties. Journal of Chemical Information and Modeling 2012;52(11):2950-2957, doi:10.1021/ci300447c
• Yen W, Williamson J, Bertram EH, et al. A comparison of three NMDA receptor antagonists in the treatment of prolonged status epilepticus. Epilepsy Research 2004;59(1): 43-50, doi:https://doi.org/10.1016/j.eplepsyres.2004.03. 004
• Lévesque M, Salami P, Behr C, et al. Temporal lobe epileptiform activity following systemic administration of 4-aminopyridine in rats. Epilepsia 2013;54(4):596-604, doi:10.1111/epi.12041
• Myers TL, Gonzalez OC, Stein JB, et al. Characterizing Concentration-Dependent Neural Dynamics of 4-Aminopyridine-Induced Epileptiform Activity. Epilepsy journal 2018;4(2), doi:10.4172/2472-0895.1000128
• Lee SY, Soltesz I. Cholecystokinin: a multi-functional molecular switch of neuronal circuits. Developmental neurobiology 2011;71(1):83-91, doi:10.1002/dneu.20815