Repurposing Thioridazine (TDZ) as an anti-inflammatory agent.

Abstract

Nuclear factor-kB (NF-kB) is a crucial transcription factor in the signal transduction cascade of the inflammatory signaling. Activation of NF-κB depends on the phosphorylation of IκBα by IκB kinase (IKKβ) followed by subsequent ubiquitination and degradation. This leads to the nuclear translocation of the p50- p65 subunits of NF-κB, 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 IKKβ represents a rational alternative strategy to the current therapies. A computer-aided drug identification protocol was followed to identify novel IKKβ 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 IKKβ inhibitors for their ability to bind and inhibit IKKβ by evaluating their docking energy. Finally, Thioridazinehydrochloride (TDZ), a potent antipsychotic drug against Schizophrenia was selected and its efficiency in inhibiting IκBα protein degradation and NF-κB activation was experimentally validated. Our study has demonstrated that TDZ blocks IκBα protein degradation and subsequent NF-κB activation to inhibit inflammation. Thus, it is a potential repurposed drug against inflammation.

• Authors: Mirza S Baig, Anjali Roy, Uzma Saqib, Sajjan Rajpoot, Mansi Srivastava, Adnan Naim, Dongfang Liu, Rohit Saluja, Syed M Faisal, Qiuwei Pan, Kati Turkowski, Gajanan N Darwhekar, Rajkumar Savai
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 12471 (08 20 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 30127400 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• NF-kappa B
• NF-KappaB Inhibitor alpha
• I-kappa B Kinase
• Thioridazine

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Cell Line
• Drug Repositioning (methods)
• Gene Expression Regulation (drug effects)
• I-kappa B Kinase (metabolism)
• Inflammation (drug therapy, metabolism)
• Male
• Mice
• NF-KappaB Inhibitor alpha (metabolism)
• NF-kappa B (metabolism)
• Phosphorylation (drug effects)
• RAW 264.7 Cells
• Signal Transduction (drug effects)
• Thioridazine (pharmacology)