Repurposing of bithionol as a potential anxiolytic agent through NF-κB suppression: Insights from behavioural, biochemical, and molecular modelling studies.

Abstract

Chronic stress activates neuroinflammatory responses through the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, rendering anxiety disorders the leading psychological disease. For the current investigation, an anxiety-related mouse model of restraint stress was adopted to analyse the potential anxiolytic activities of bithionol, a Food and Drug Administration (FDA) an approved anthelmintic drug. It is expected that bithionol should act through inhibiting the process of NF-κB activation, which reduces pro-inflammatory cytokines production. Three dosages of bithionol (25, 50, 100 mg/kg) were administered in male Swiss albino mice subjected to chronic restraint stress, of which diazepam served as the comparator anxiolytic. The behavioural tests, like the Marble Burying Test, Open Field Test (OFT), Elevated Plus Maze (EPM), Light and Dark Transition Screening test, were used for determining anxiety-like behaviours. Therapy with bithionol significantly reduced NF-κB, Tumor necrosis factor- alpha (TNF-α), as well as (Interleukin-1beta) IL-1β, while enhancing serotonin levels primarily at the highest dose of 100 mg/kg, as revealed through biochemical analysis of brain homogenates. These observations suggest that bithionol exhibits dose-dependent anxiolytic activity, possibly through suppression of the NF-κB pathway as well as neuroinflammatory reductions. Molecular modelling study has been performed to gain the insights of molecular level interactions between bithionol and NF-κB, TNF-α and IL-1β. Thus, the repurposing of bithionol for anxiety disorders is investigated.