Biological Evaluation of Aegle marmelos Fruit Extract and Isolated Aegeline in Alleviating Pain–Depression Dyad: In Silico Analysis of Aegeline on MAO-A and iNOS

[Image: see text] Pain and depression have been assessed to co-occur in up to 80% of patients, and this comorbidity is more debilitating and pricier for the patients as compared to either of these disorders alone. Aegle marmelos is a well-known medicinal plant with a broad spectrum of pharmacological activities. Aegeline is a relatively unexplored molecule present in Aegle marmelos. Therefore, the current investigation aims to explore the potential of Aegle marmelos fruit extract (AMFE) and isolated aegeline against the reserpine-induced pain–depression dyad. In the current investigation, aegeline was isolated from AMFE, followed by spectroscopic characterization, i.e., using NMR and mass analyses. AMFE (200 mg kg(–1) p.o) and aegeline (10 mg kg(–1) p.o.) were administered to reserpinized (0.5 mg kg(–1) s.c.) mice, and clorgyline (3 mg kg(–1) i.p.) was taken as the standard drug. AMFE and aegeline significantly alleviated the reserpine-induced reduction in a pain threshold and an increase in immobility as observed in behavioral tests of pain and depression, respectively. In silico molecular docking studies of aegeline showed a good binding interaction at the active sites of MAO-A and iNOS. The in vivo analysis showed that AMFE and aegeline treatment significantly decreased the monoamine oxidase-A (MAO-A) activity, serum interleukin-6 (IL-6) level, and lipid peroxidation, along with an increase in the reduced glutathione level in comparison to the reserpine-treated group. Immunofluorescence studies also showed that AMFE and aegeline abrogated the reserpine-induced increase in iNOS expression. Conclusively, the results delineate that AMFE and aegeline might exert a protective effect via downregulating the MAO-A hyperactivity, IL-6 level, oxidative and nitrosative stress.