Quercetin and/or Ascorbic Acid Modulatory Effect on Phenobarbital-Induced Sleeping Mice Possibly through GABAA and GABAB Receptor Interaction Pathway

Abstract

Background: Depressive disorder is a recurrent illness that affects large numbers of the general population worldwide. In recent years, the goal of depression treatment has moved from symptomatic response to that of full remission. However, treatment-resistant depression is a major challenge in the treatment of depression or depression-related disorders. Consensus opinion, therefore, suggests that effective combined aggressive initial treatment is the most appropriate strategy. Objectives: This study aimed to evaluate the effects of quercetin (QUR) and/or ascorbic acid (AA) on Phenobarbital-induced sleeping mice. Methods: QUR (50 mg/kg) and/or AA (25 mg/kg) with or without intraperitoneally pre-treated with GABA receptor agonist (diazepam: 2 mg/kg, i.p.) or antagonist (Flumazenil: 2.5 mg/kg, i.p.) to underscore the effects, as well as the possible involvement of the GABA receptor in the modulatory action of QUR and AA in sleeping mice. Additionally, an in silico study was undertaken to predict the involvement of GABA receptors in the sleep mechanism. Results: Findings suggest that the pretreatment of QUR and AA modulated the onset and duration of action of the standard drugs in experimental animals. The acute administration of QUR and/or AA significantly (p < 0.05) reversed the DZP-mediated onset of action and slightly reversed the duration of sleep time in comparison to the vehicle (control) group. A further combination of QUR or AA with the FLU resulted in an enhancement of the onset of action while reducing the duration of action, suggesting a FLU-like effect on the test animals. In in silico studies, AA and QUR showed good to moderate binding affinities with GABAA and GABAB receptors. Conclusions: Both QUR and AA produced a stimulatory-like effect on mice, possibly through the GABAA and GABAB receptor interaction pathways. Further studies are necessary to verify this activity and clarify the exact mechanism of action(s) involved.

Amentoflavone derivatives significantly act towards the main protease (3CLPRO/MPRO) of SARS-CoV-2: in silico admet profiling, molecular docking, molecular dynamics simulation, network pharmacology

“…Amentoflavone (biflavonoid) is one of the plant derivatives compounds that were isolated by Okigawa et al [ 16 ], and due to a wider range of bioactivities, it has drawn much attention among the scientific community [ 3 , 66 , 67 ]. A compound should have some fundamental properties for becoming an ideal anti-COVID-19 drug candidate [ 44 ] such as (i) restriction ability of viral entrance, thereby inhibiting cellular attachment; (ii) inhibition of viral replication inside the host cells; (iii) cytotoxic effects on the existing viruses; and (iv) protection of the host normal cells from the viral origin oxidative stress and inflammatory responses. And the compound amentoflavone is the evidence that followed all of these pathways and performed as potential anti-COVID-19 therapeutics; even not only this compound alone but also its derivatives showed the antioxidant [ 68 , 69 ] and anti-inflammatory [ 3 , 70 – 72 ] activities.…”

“…BIOVIA Discovery Studio tool (version 4.5) was applied to determine the interactions between “protein–ligand complex,” where mainly evaluate the diverse interactions (hydrogen-, hydrophobic-, pi-alkali-bond, and so on), and most importantly here used was the combined file which was collected from the PyMOL visualizer tool [ 44 ].…”

Antidepressant Potential of Quercetin and its Glycoside Derivatives: A Comprehensive Review and Update

“…Besides monoaminergic neurotransmitters, quercetin can improve depression-like behaviors by regulating choline, amino acid neurotransmitters, and their corresponding receptors. Moreover, quercetin has a good binding affinity for GABAα receptors and attenuates depressive symptoms by antagonizing somatostatin to stimulate GABAergic interneurons (Hossain et al, 2021). Previous studies have also confirmed that quercetin can reduce the levels of acetylcholinesterase (AchE) in animals (Samad et al, 2018) and the hyperactivity of cholinergic nerves, leading to hypoadrenergic function, which would cause depression (Teneralli et al, 2021).…”

“…Regarding the mechanisms, current studies have focused on inhibiting the expression of corticotropin-releasing factor messenger ribonucleic acid (CRF mRNA) (Bhutada et al, 2010;Kawabata et al, 2010), controlling the levels of interleukin (IL)-1β to prevent continued activation of the HPA axis (Mkhize et al, 2017), and promoting GABAergic neurons to regulate the termination of the HPA axis in response to stress (Hossain et al, 2021). These mechanisms can not be simply integrated and the precise mechanisms by which quercetin inhibits the hyperactivity of the HPA axis are not fully understood, so further studies are required.…”

Anxiolytic-like Effect of Quercetin Possibly through GABA Receptor Interaction Pathway: In Vivo and In Silico Studies

“…Our findings also suggest an opposite effect of DZP for the FLU-treated animals, which was confirmed by the increased number of hole crosses and swings in mice. Further, the co-treatment of DZP and/or QUR with FLU was observed to decrease the test parameters in comparison to the FLU group in these test models: QUR produced a moderate flumazenil (FLU)-like effect in the test animals, and a number of studies have demonstrated that QUR binds with GABAA and B receptors but exerts an antagonistic effect similar to FLU [ 33 , 34 ]. Therefore, when DZP was administered with QUR, QUR exposed a calming effect.…”