TY - JOUR

T1 - Resveratrol and Its Metabolite as Potential Allosteric Regulators of Monoamine Oxidase A Activity in the Brain and Liver Under Chronic Predator Stress

AU - Novak, Jurica

AU - Tseilikman, Olga B.

AU - Shatilov, Vladislav A.

AU - Zhukov, Maxim S.

AU - Shevyrin, Vadim A.

AU - Khismatullina, Zuhra R.

AU - Fedorova, Albina M.

AU - Patrikyan, Georgiy N.

AU - Khaibullin, Timur L.

AU - Tseilikman, Vadim E.

N1 - This work was supported by the Russian Scientific Foundation, regional grant, Chelyabinsk Region (#23-15-20040). The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethical Committee for Animal Experiments of South Ural State University, Chelyabinsk, Russia (project #0425-2018-0011 of 17 May 2018, protocol number 36/645).

PY - 2025/5/14

Y1 - 2025/5/14

N2 - Background: Resveratrol has been shown to modulate stress-related anxiety by reducing brain monoamine oxidase A (MAO-A) activity. However, the molecular mechanism underlying this neurochemical effect remains unknown. In this study, we employed in silico approaches to investigate the binding affinity of resveratrol and its predominant blood metabolite, resveratrol glucuronide, to specific sites on MAO-A. Methods: For the in silico analysis, we employed molecular docking and molecular dynamics simulations. Within the liver–brain axis, we investigated the role of hepatic MAO-A in the development of anxiety. The activity of whole-brain MAO-A was compared with its activity in specific brain regions, including the amygdala, hippocampus, and prefrontal cortex. Results: Our findings suggest the presence of an allosteric site on the enzyme that accommodates these compounds. Furthermore, in vivo experiments demonstrated that high-dose resveratrol suppresses MAO activity not only in the brain but also in the liver of stress-exposed rats. The in vivo results are interpreted in the context of an allosteric site on MAO-A in both the brain and liver, which may mediate the interaction with resveratrol and its metabolite. Conclusions: The primary outcomes of the study include the identification of the role of hepatic MAO-A in the development of anxiety-like behavior, as well as the determination of resveratrol dose ranges at which it functions as an allosteric modulator of MAO-A activity.

AB - Background: Resveratrol has been shown to modulate stress-related anxiety by reducing brain monoamine oxidase A (MAO-A) activity. However, the molecular mechanism underlying this neurochemical effect remains unknown. In this study, we employed in silico approaches to investigate the binding affinity of resveratrol and its predominant blood metabolite, resveratrol glucuronide, to specific sites on MAO-A. Methods: For the in silico analysis, we employed molecular docking and molecular dynamics simulations. Within the liver–brain axis, we investigated the role of hepatic MAO-A in the development of anxiety. The activity of whole-brain MAO-A was compared with its activity in specific brain regions, including the amygdala, hippocampus, and prefrontal cortex. Results: Our findings suggest the presence of an allosteric site on the enzyme that accommodates these compounds. Furthermore, in vivo experiments demonstrated that high-dose resveratrol suppresses MAO activity not only in the brain but also in the liver of stress-exposed rats. The in vivo results are interpreted in the context of an allosteric site on MAO-A in both the brain and liver, which may mediate the interaction with resveratrol and its metabolite. Conclusions: The primary outcomes of the study include the identification of the role of hepatic MAO-A in the development of anxiety-like behavior, as well as the determination of resveratrol dose ranges at which it functions as an allosteric modulator of MAO-A activity.

KW - allostery

KW - monoamine oxidase

KW - resveratrol

KW - serotonin

KW - trans-resveratrol-3-O-glucuronide

UR - https://www.mendeley.com/catalogue/b639d37e-247a-36f0-8dbc-b5cbf9ef90a7/

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105006814135&origin=inward

U2 - 10.3390/biomedicines13051196

DO - 10.3390/biomedicines13051196

M3 - Article

C2 - 40427023

VL - 13

JO - Biomedicines

JF - Biomedicines

SN - 2227-9059

IS - 5

M1 - 1196

ER -