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

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.

Anahtar Kelimeler:

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

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,

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