<i>Nardostachys jatamansi</i> Mitigates Radiation-induced Depressive Behaviour: Evidence from Behavioural Assessment and Computational Insights into Multi-target Mechanisms

Background: Radiation-induced depression is a significant neuropsychiatric consequence following therapeutic exposure to ionising radiation. Nardostachys jatamansi (N. jatamansi), a medicinal herb widely used in Ayurvedic medicine, is well-recognised for its neuroprotective and antidepressant properties. Aim: This study aimed to evaluate the antidepressant activity of N. jatamansi Ethanolic Extract (NJEE) in a mouse model of electron beam radiation-induced depression and to explore its potential molecular mechanisms against key targets of depression using computational approaches. Methods: Mice that were exposed to electron beam radiation were assessed for depressive-like behaviours using the Forced Swim Test (FST) and Tail Suspension Test (TST). NJEE was administered post-radiation, and behavioural outcomes were recorded. To elucidate the molecular basis of its antidepressant effects, molecular docking of 248 phytochemicals from N. jatamansi was performed against depression-associated targets: the GABAB receptor, Monoamine Oxidase A (MAO-A), and Monoamine Oxidase B (MAO-B). Compounds with high docking scores were further analysed using 100 ns molecular dynamics simulations and binding free energy calculations. Results: NJEE-treated mice exhibited significantly reduced immobility time in both the FST and TST, indicating notable antidepressant activity. Docking studies revealed that 76, 107, and 111 phytochemicals demonstrated stronger binding affinities toward the GABAB receptor, MAO-A, and MAO-B, respectively, compared to standard ligands. Remarkably, 73 compounds showed binding interactions with all three targets. Molecular dynamics simulations confirmed the stability of the top ligand-receptor complexes, and binding energy analyses further supported the potential efficacy of these compounds. Conclusion: NJEE exhibits significant antidepressant effects in a radiation-induced depression model in mice. In silico findings suggest that multiple phytoconstituents in NJEE may modulate key molecular targets implicated in depression, highlighting its potential as a multi-target therapeutic agent for depressive disorders associated with radiation exposure. Major Findings: NJEE showed protective activity against the radiation-induced depression model in mice. In silico analysis revealed that its phytoconstituents could interact with multiple key targets of depression with high affinity, suggesting its potential as a multi-target therapeutic agent.