Tangeretin Improves the Memory of Swiss Mice, Suggesting Potential Molecular Interventions Through Animal Behavior Assessments and In Silico Studies

Abstract

Introduction: Tangeretin (TAN), a polymethoxylated flavone from citrus peels, exhibits neuroprotective, anti-inflammatory, and antioxidant properties. This study aims to evaluate the memory-enhancing effects of TAN in Swiss mice and explore its potential molecular interactions with the D₂ dopamine (DOP) receptor through in vivo behavioral assessments and in silico approaches.

Methods: Swiss mice were administered TAN (10 and 20 mg/kg), DOP (22 mg/kg), and olanzapine (OLN) (2 mg/kg), alone and in combinations per orally (p.o.), followed by cognitive assessments using marble burying, dust removal, and trained swimming tests. In silico studies included molecular docking against the D₂ receptor (PDB: 6CM4), pharmacokinetics (SwissADME, pkCSM), and toxicity predictions (ProTox-3).

Results: TAN significantly (p < 0.05) improved cognitive functions, including memory, anxiety, and motor coordination, in a dose-dependent manner, with 20 mg/kg showing the most notable effect. The combination of TAN-10 with DOP-22 enhanced these benefits, whereas TAN-10 with OLN-2 reduced cognitive improvements. TAN-treated Swiss mice showed better performance in marble burying, dust removal, and trained swimming tests, indicating enhanced memory, problem-solving, and motor coordination. These results suggest TAN's potential in cognitive enhancement, particularly with DOP-22. No deaths were observed in any treatment group, and all treated animals exhibited normal physiological activity with no signs of acute toxicity. In silico studies revealed that TAN exhibited the strongest binding affinity (BA) (-6.6 kcal/mol) with the D₂ receptor, forming multiple hydrogen bonds (HBs), which indicates its potential mechanism for memory enhancement via dopaminergic modulation. Pharmacokinetic analyses also showed that TAN has favorable ADMET properties, including high gastrointestinal absorption, blood-brain barrier penetration, and low toxicity.

Conclusion: These findings highlight TAN's potential as a promising therapeutic candidate for memory-related disorders, warranting further clinical exploration.

Keywords: dopamine receptor; memory‐enhancing effect; molecular interactions; tangeretin.

FIGURE 1

The 2‐dimensional chemical structures of tangeretin, dopamine, and olanzapine.

FIGURE 2

The 2D and 3D structures of the non‐bond interactions among dopamine, olanzapine, and tangeretin with the selected receptor (6CM4).

FIGURE 3

Bioavailability radar related to physicochemical properties of tangeretin, dopamine, and olanzapine [the physicochemical space that is appropriate for oral bioavailability is the colored zone; SIZE: 150 g/mol < MV < 500 g/mol; LIPO (lipophilicity): −7 < XLOGP3 < + 5.0; INSOLU (insolubility): −6 < log S (ESOL) < 0; POLAR (polarity): 20 Å² < TPSA < 130 Å²; IN‐SATU (in saturation): 0.25 < fraction Csp3 < 1; FLEX (flexibility): 0 < num. rotatable bonds < 9].

FIGURE 4

(a) Number of marbles buried; (b) amount of dust removed; (c) time to reach to the target point observed in different treatment groups of animals.

FIGURE 5

The possible memory‐enhancing effect mechanism of tangeretin. TAN alone involves its interaction with the D₂ receptor, enhancing dopamine signaling by promoting G‐protein activation, leading to increased excitation and gene expression, which supports memory function. When TAN is combined with DOP, the effect is amplified as DOP further boosts dopamine availability in the synaptic cleft, enhancing D₂ receptor activation. This synergistic interaction strengthens the signaling cascade, resulting in greater neuronal excitation and gene expression, ultimately leading to a more pronounced memory‐enhancing effect. DOP, Dopamine; OLN, Olanzapine; TAN, Tangeretin.