Repurposing Thioridazine (TDZ) as an anti-inflammatory agent

Nuclear factor-kB (NF-kB) is a crucial transcription factor in the signal transduction cascade of the inflammatory signaling. Activation of NF-kappa B depends on the phosphorylation of I kappa B alpha by I kappa B kinase (IKK beta) followed by subsequent ubiquitination and degradation. This leads to the nuclear translocation of the p50-p65 subunits of NF-kappa B, and further triggers pro-inflammatory cytokine gene expression. Thus, in the need of a more effective therapy for the treatment of inflammatory diseases, specific inhibition of IKK beta represents a rational alternative strategy to the current therapies. A computer-aided drug identification protocol was followed to identify novel IKK beta inhibitors from a database of over 1500 Food and Drug Administration (FDA) drugs. The best scoring compounds were compared with the already known high-potency IKK beta inhibitors for their ability to bind and inhibit IKK beta by evaluating their docking energy. Finally, Thioridazinehydrochloride (TDZ), a potent antipsychotic drug against Schizophrenia was selected and its efficiency in inhibiting I kappa B alpha protein degradation and NF-kappa B activation was experimentally validated. Our study has demonstrated that TDZ blocks I kappa B alpha protein degradation and subsequent NF-kappa B activation to inhibit inflammation. Thus, it is a potential repurposed drug against inflammation.