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. 2025 Feb;31(2):e70276.
doi: 10.1111/cns.70276.

Anxiolytic Activity of Morellic Acid: Modulation of Diazepam's Anxiolytic Effects, Possibly Through GABAergic Interventions

Md Shimul Bhuia  1   2 , Tanzila Akter Eity  2   3 , Raihan Chowdhury  1   2 , Siddique Akber Ansari  4 , Mehedi Hasan Bappi  2   5 , Md Anin Nayeem  1   2 , Farjana Akter  2   6 , Muhammad Torequl Islam  1   2   7
Affiliations

Anxiolytic Activity of Morellic Acid: Modulation of Diazepam's Anxiolytic Effects, Possibly Through GABAergic Interventions

Md Shimul Bhuia et al. CNS Neurosci Ther. 2025 Feb.

Abstract

Background: Numerous studies suggest that morellic acid (MOR), highly available in Garcinia plants, has different physiological activities, including anti-cancer, anti-oxidant, and anti-microbial activity.

Aim: In this investigation, we aimed to demonstrate the anxiolytic activity, along with the mechanism behind this activity of MOR, using in vivo and in silico studies.

Methods: For this, we used different doses of MOR (5 and 10 mg/kg) and administered this drug intraperitoneally to Swiss albino mice (male and female). Diazepam (DZP), a positive allosteric modulator of the GABAA receptor, was used as a positive control at a dose of 2 mg/kg (i.p), and vehicle was used as a control group. In this test, various test protocols are used to assess the behavioral patterns of mice, including swing, hole cross, light-dark testing, and open field testing.

Results: This investigation revealed that MOR remarkably reduced the locomotor activity of mice in a dose-dependent manner and produced calming behaviors like DZP. However, the findings showed that the combination of MOR and DZP synergistically reduced the locomotion of mice compared to the single therapy. On the other hand, from the computational study, the result demonstrated that MOR exhibited the highest binding scores (-9.2 kcal/mol) towards the GABAA receptor α3 subunit and -7.6 kcal/mol towards the GABAA α2 receptor. Whereas, DZP showed -6.6 and -7.3 kcal/mol docking affinity and FLU exerted -6.2 and -6.3 kcal/mol docking scores towards the GABAA receptor α2 and α3 subunits, respectively. The ligand interacted with the receptor by forming different hydrogen and hydrophobic bonds.

Conclusion: However, it is recommended that more precise and comprehensive preclinical investigations be required to demonstrate the exact mechanism behind the anxiolytic effects and conduct clinical trials to determine efficacy and safety.

Keywords: GABAergic transmission; anxiety; molecular docking; morellic acid; neuroprotective; xanthones 3.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Study outline for anxiolytic test in Swiss albino mice.
FIGURE 2
FIGURE 2
The chemical structures of diazepam, flumazenil, and morellic acid.
FIGURE 3
FIGURE 3
Behavioral observations across test and control groups: (a) Number of square crosses (NSC), (b) number of grooming (NG), and (c) Number of rearing (NR). [Values are presented as mean ± standard error of the mean (SEM). Statistical analysis was performed using one‐way ANOVA followed by Student–Newman–Keuls post hoc test with multiple comparisons at 95% confidence intervals; Degree of freedom (DF): 35; p < 0.05 when *compared to the control (vehicle) group; acompared to the DZP‐2; bcompared to the FLU‐0.10; ccompared to the MOR‐5; dcompared to the MOR‐10; DZP‐2: Diazepam (2 mg/kg); FLU‐0.10: Flumazenil (0.10 mg/kg); MOR‐5 and 10: Morellic acid (5 and 10 mg/kg)].
FIGURE 4
FIGURE 4
Behavioral observations across test and control groups: (a) Number of swing (NS), (b) number of hole cross (NHC), (c) dark residence time (DRT) [Values are presented as mean ± standard error of the mean (SEM). Statistical analysis was performed using one‐way ANOVA followed by Student–Newman–Keuls post hoc test with multiple comparisons at 95% confidence intervals; Degree of freedom (DF): 35; p < 0.05 when *compared to the control (vehicle) group; acompared to the DZP‐2; bcompared to the FLU‐0.10; ccompared to the MOR‐5; dcompared to the MOR‐10; DZP‐2: Diazepam (2 mg/kg); FLU‐0.10: Flumazenil (0.10 mg/kg); MOR‐5 and 10: Morellic acid (5 and 10 mg/kg)].
FIGURE 5
FIGURE 5
Ramachandran plot of the homology‐modeled GABAA receptor: (a) α2 subunit; (b) α3 subunit.
FIGURE 6
FIGURE 6
2D and 3D views of the receptor binding sites with the names of non‐bond interactions and amino acid residues of morellic acid, flumazenil, and diazepam‐GABAA (α2 and α3) receptor complex.
FIGURE 7
FIGURE 7
(a) Overview of the physicochemical, toxicological, and pharmacokinetic characteristics of morellic acid. The colored zone indicates the ideal physicochemical space for oral bioavailability. The parameters are defined as follows: SIZE: 150 g/mol2 < TPSA < 130 Å2; FLEX (Flexibility): 0 < num. rotatable bonds < 9. (b) The network chart is intended to quickly illustrate the connection between the selected compound (morellic acid and diazepam) and predicted activities. Abbreviation: bbb, blood brain barrier; carcino, carcinogenicity; cardio, cardiotoxicity; clinical, clinical toxicity; cyto, cytotoxicity; dili, drug‐induced liver injury; eco, ecotoxicity; immuno, immunotoxicity; mutagen, mutagenicity; nephro, nephrotoxicity; neuro, neurotoxicity; nutri, nutritional toxicity; respi, respiratory toxicity.
FIGURE 8
FIGURE 8
The possible anxiolytic mechanisms of morellic acid through GABAA receptors. [Morellic acid (MOR) and diazepam (DZP) bind with the allosteric sites of GABAA receptors and significantly hinder the Cl− influx into the postsynaptic neuron, causing neuronal hyperpolarization resulting in anxiolytic activity].
See this image and copyright information in PMC

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