Antipsychotic effect of Aegiceras corniculatum (L.) Blanco: Evidence from murine behavioral assays and computational studies

Introduction: Antipsychotic therapy targets the mesolimbic dopaminergic hyperactivity observed in schizophrenia. Drugs such as olanzapine (Zyprexa) alleviate positive symptoms by suppressing this pathway, although they are often associated with adverse effects, including psychomotor slowing. Notably, In Traditional Chinese Medicine (TCM), Aegiceras corniculatum (蠟燭果;桐花樹) is documented in classical materia medica for treating pain, swelling, rheumatism, asthma, and diabetes. Its traditional role in analgesia and nociception suggests engagement of central pain-modulating pathways, and together with reported neuromodulatory properties, provides a rationale for evaluating its relevance in schizophrenia. Methods: Ethanolic leaf extract of A. corniculatum (ACEE) was evaluated in dopamine-induced mouse models using marble burying, dust removal, and trained swim tests. Effects were compared with olanzapine (Zyprexa) (OLN-2) and combination treatments. Phytoconstituents were identified via GC–MS, while molecular docking and ADMET profiling assessed interactions with dopamine D₂ receptors, pharmacokinetics, and safety. Results: Dopamine (DOP-22) significantly increased compulsive behaviors (marble burying: 13.8 ± 1.5 vs. 10.8 ± 1.9 in controls; dust removal: 141.4 ± 9.3 g vs. 107.1 ± 14.3 g, p < 0.05). OLN-2 reduced both (6.0 ± 0.6 marbles; 42.5 ± 4.9 g). ACEE produced dose-dependent reductions (9.3 ± 1.8 and 8.0 ± 1.8 marbles; 87.3 ± 8.4 g and 64.4 ± 11.2 g). Combined ACEE-250 and OLN-2 yielded stronger suppression (5.7 ± 0.8 marbles; 54.2 ± 6.8 g). In the trained swim test, dopamine improved performance (6.8 ± 2.1 s vs. 10.3 ± 1.7 s), while OLN-2 impaired it (18.7 ± 2.4 s). ACEE caused moderate slowing (15.4 ± 1.3 s), suggesting partial preservation of psychomotor function. Docking revealed BOPC as the strongest D₂ ligand (-9.1 kcal/mol), while more abundant compounds (PPD, BEA, MDT) showed moderate affinities with favorable ADMET characteristics. Conclusion: ACEE demonstrated antipsychotic-like activity through dopaminergic modulation, with an additive effect when combined with OLN-2, and showed a milder impact on psychomotor performance. Supported by traditional use and preliminary modern analyses, A. corniculatum warrants further investigation as a potential complementary source of dopaminergically active compounds.