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    Fatty acid amide hydrolase inhibition and N-arachidonoylethanolamine modulation by isoflavonoids: A novel target for upcoming antidepressants.

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    Author
    Zada, Wahid
    VanRyzin, Jonathan W
    Perez-Pouchoulen, Miguel
    Baglot, Samantha L
    Hill, Matthew N
    Abbas, Ghulam
    Clark, Sarah M
    Rashid, Umer
    McCarthy, Margaret M
    Mannan, Abdul
    Date
    2022-08-26
    Journal
    Pharmacology Research & Perspectives
    Publisher
    British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1002/prp2.999
    Abstract
    Modulation of the endocannabinoid system (ECS) is a novel putative target for therapeutic intervention in depressive disorders. Altering concentrations of one of the principal endocannabinoids, N-arachidonoylethanolamine, also known as anandamide (AEA) can affect depressive-like behaviors through several mechanisms including anti-inflammatory, hormonal, and neural circuit alterations. Recently, isoflavonoids, a class of plant-derived compounds, have been of therapeutic interest given their ability to modulate the metabolism of the endogenous ligands of the ECS. To determine the therapeutic potential of isoflavonoids, we screened several candidate compounds (Genistein, Biochanin-A, and 7-hydroxyflavone) in silico to determine their binding properties with fatty acid amide hydrolase (FAAH), the primary degrative enzyme for AEA. We further validated the ability of these compounds to inhibit FAAH and determined their effects on depressive-like and locomotor behaviors in the forced swim test (FST) and open field test in male and female mice. We found that while genistein was the most potent FAAH inhibitor, 7-hydroxyflavone was most effective at reducing immobility time in the forced swim test. Finally, we measured blood corticosterone and prefrontal cortex AEA concentrations following the forced swim test and found that all tested compounds decreased corticosterone and increased AEA, demonstrating that isoflavonoids are promising therapeutic targets as FAAH inhibitors.
    Data Availibility
    The authors confirm that the data that support the findings of this study are available within the article and its supplementary materials.
    Rights/Terms
    © 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.
    Keyword
    anxiety
    depression
    endocannabinoids
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/19643
    ae974a485f413a2113503eed53cd6c53
    10.1002/prp2.999
    Scopus Count
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