Conessine ameliorates anxiety and depression-like behaviors in reserpine-induced zebrafish (Danio rerio) through modulation of oxidative stress, neuroinflammation and BDNF signaling: experimental and computational evidence

Background Depression and anxiety are common neuropsychiatric disorders associated with oxidative stress, neuroinflammation, and impaired neuroplasticity. Conessine, a plant-derived steroidal alkaloid with reported antioxidant and anti-inflammatory properties, has not been sufficiently investigated for its effects on anxiety- and depression-like behaviours. The current study investigated the effects of conessine in a reserpine-induced zebrafish model using behavioural, biochemical, molecular, histopathological, and computational approaches. Methods Adult zebrafish were exposed to reserpine and subsequently treated with different concentrations of conessine. Behavioural responses were assessed using the Novel Tank Test and Light-Dark Test, while oxidative stress markers, monoamine oxidase (MAO) activity, brain histopathology, and the expression of TNF-α, IL-1β, and BDNF were evaluated. Molecular docking and 100-ns molecular dynamics simulations were performed to investigate the interaction of conessine with IKKβ. Results Conessine treatment increased exploratory behaviour and decreased freezing behaviour in reserpine-exposed zebrafish. It also increased antioxidant enzyme activity, decreased MAO activity, and improved histopathological alterations. Furthermore, conessine decreased the expression of TNF-α and IL-1β and increased BDNF expression. Computational analysis indicated favourable binding of conessine to IKKβ and a stable protein–ligand interaction during molecular dynamics simulation. Conclusion Overall, conessine attenuated several behavioural, biochemical, inflammatory, and histopathological alterations associated with reserpine exposure. These findings provide preliminary preclinical evidence supporting further investigation of conessine.