Antidepressant‐Like Effects of Hydroxychavicol‐Enriched <i>Piper betle</i> L. Leaf Extract in Chronic Mild Stress–Induced Rodent Models and Possible Mechanism(s) of Action Involved

This study discovers the potential of hydroxychavicol-enriched fraction of Piper betle L. leaf extract (HCRF) as an antidepressant alternative in chronic unpredictable mild stress (CUMS) rodent models with biochemical parameters. It also focused on possible mechanisms through molecular simulation via the anti-inflammatory pathway and in silico pharmacokinetic study. HCRF is isolated from betel leaves, and Swiss albino mice were orally administrated with doses of 50 mg/kg and 100 mg/kg of body weight (bw) for 5 weeks before the CUMS protocols, respectively. In silico investigation is done with pkCSM software for the ADMET study, and molecular docking is performed on hydroxychavicol with target protein 2ZOQ in Schrödinger. HCRF prevented the irregular behaviors acquired in CUMS model, with reduced hypoactivity and sucrose anhedonia. HCRFs of 50 and 100 mg/kg bw diminished the upsurges in the level of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) in the serum associated with stress. HCRF of 100 mg/kg bw improved inflammation in the brain by plummeting the malonaldehyde and increasing the glutathione via revering oxidative stress. HCRF exhibited an activity similar to antidepressants and might be a consequence of the anti-inflammatory action. The molecular simulation and pharmacokinetic study ensured a probable mechanistic approach of hydroxychavicol in CUMS-associated depression through inflammatory pathways.