Sains Malaysiana 51(10)(2022): 3383-3399

http://doi.org/10.17576/jsm-2022-5110-22

Antidepressant Potential of Daidzein through Modulation of Endocannabinoid System by Targeting Fatty Acid Amide Hydrolase

(Potensi Anti-kemurungan Daidzein melalui Modulasi Sistem Endokanabinoid dengan Menyasarkan Asid Lemak Amida Hidrolase)

WAHID ZADA¹, GHULAM MURTAZA², GHAZALA IQBAL³, GHULAM ABBAS⁴, SHUJAAT ALI KHAN¹ & ABDUL MANNAN^1,*

¹Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus 22060, Pakistan

²Department of Pharmacy, COMSATS University Islamabad, Lahore Campus 5400, Pakistan

³Department of Pharmacy, Kohat University of Science and Technology, Kohat, Pakistan

⁴Department of Pharmacology, Faculty of Pharmacy Ziauddin University, Karachi Pakistan

Diserahkan: 17 Mac 2022/Diterima: 30 Mei 2022

Abstract

In recent decades, the identification of natural compounds that modulate the endocannabinoid system by fatty acid amide hydrolase (FAAH) inhibition has provided an interesting area of research. Daidzein, which is an isoflavone, has neurobiological activities that are effective against several neurological disorders which include depression. This study aimed to investigate the FAAH inhibitory activity of Daidzein through in-silico analysis via Molecular Operating Environment software together with the in-vitro FAAH inhibitory assay. Furthermore, the anti-depressive effect of Daidzein (20 mg/kg) was examined via open field test and forced swim test in both male and female mice groups. Finally, the level of depression and stress was measured by the plasma corticosterone level.  Molecular docking has shown the probable binding of Daidzein with the FAAH enzyme via its ser-ser-lys catalytic triad. Daidzein binds to the active pocket of FAAH with excellent binding energy of -64.77 Kcal/mol and binding affinity of -11.77 Kcal/mol. The findings reported that Daidzein inhibited the FAAH enzyme with IC₅₀ value at 1.3±0.13 µM concentration. The open field test showed that Daidzein had no significant effect on locomotory activity in both male and female groups compared to fluoxetine and Arch-5HT group. Daidzein has significantly decreased the immobility time in forced swim test, which is an indicator of an anti-depressive effect. The corticosterone level that regulates depression was significantly decreased in both male and female Daidzein-treated mice groups. This study highlighted the role of Daidzein as a therapeutic agent for depression via the inhibition of FAAH and modulation of corticosterone levels.

Keywords: Corticosterone; depression; endocannabinoid system; forced swim test; HPA-axis; molecular docking; open field test

Abstrak

Dalam beberapa dekad kebelakangan ini, pengenalpastian sebatian semula jadi yang memodulasi sistem endokanabinoid oleh perencatan asid lemak amide hidrolase (FAAH) telah menyediakan bidang penyelidikan yang menarik. Daidzein yang merupakan isoflavon, mempunyai aktiviti neurobiologi yang berkesan terhadap beberapa gangguan neurologi termasuk kemurungan. Penyelidikan ini bertujuan untuk mengkaji aktiviti perencatan FAAH Daidzein melalui analisis in-silico melalui perisian Persekitaran Kendalian Molekul bersama-sama dengan ujian perencatan FAAH in-vitro. Tambahan pula, kesan anti-kemurungan Daidzein (20 mg/kg) telah diperiksa melalui ujian lapangan terbuka dan ujian berenang paksa pada kumpulan tikus jantan dan betina. Akhirnya, tahap kemurungan dan tekanan diukur dengan tahap kortikosteron plasma. Dok molekul telah menunjukkan kemungkinan pengikatan Daidzein dengan enzim FAAH melalui triad pemangkin ser-ser-lys. Daidzein mengikat pada poket aktif FAAH dengan tenaga pengikat yang sangat baik iaitu -64.77 Kcal/mol dan pertalian mengikat -11.77 Kcal/mol. Hasil menunjukkan bahawa Daidzein merencat enzim FAAH dengan nilai IC₅₀ pada kepekatan 1.3±0.13 µM. Ujian lapangan terbuka menunjukkan bahawa Daidzein tidak mempunyai kesan yang signifikan terhadap aktiviti lokomotor pada kedua-dua kumpulan jantan dan betina berbanding kumpulan fluoksetin dan Arch-5HT. Daidzein telah mengurangkan dengan ketara masa pergerakan dalam ujian berenang paksa yang merupakan penunjuk kesan anti-kemurungan. Tahap kortikosteron yang mengawal kemurungan telah menurun dengan ketara pada kumpulan tikus jantan dan betina yang dirawat Daidzein. Kajian ini menekankan peranan Daidzein sebagai agen terapeutik untuk kemurungan melalui perencatan FAAH dan modulasi tahap kortikosteron.

Kata kunci: Dok molekul; kemurungan; kortikosteron; paksiHPA; sistem endokanabinoid; ujian berenang paksa; ujian lapangan terbuka

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