Abstract
BackgroundPenfluridol, isolated from an FDA-approved small-molecule drug library as an inhibitor of tumor necrosis factor α (TNFα)-stimulated NF-κB activation, is clinically used to treat chronic schizophrenia and related disorders. This study is aimed to investigate the therapeutic effect of penfluridol on TNFα-stimulated inflammatory autoimmune diseases, particularly inflammatory arthritis.MethodsVarious in vitro studies to confirm the inhibitory effect of penfluridol on TNFα-induced NF-κB activity in bone marrow-derived macrophages or Raw 264.7 macrophage cell line. In vivo studies assessed the therapeutic effects of penfluridol in various disease models, including TNFα transgenic mice, collagen-induced arthritis, DSS-induced colitis, and TNBS-induced colitis. Identification and characterization of the binding of penfluridol to acid sphingomyelinase using bioinformatics and drug affinity responsive target stability assay. Acid sphingomyelinase activity assays to reveal penfluridol-mediated inhibition of acid sphingomyelinase activity. siRNA knockdown experiments to illustrate the dependence of penfluridol’s anti-TNF activity on acid sphingomyelinase.ResultsPenfluridol effectively inhibited TNFα-induced NF-κB activation in vitro and alleviated the severity of arthritis and colitis in vivo. Mechanistic studies revealed that penfluridol bound to acid sphingomyelinase and inhibited its activation. In addition, knockdown of acid sphingomyelinase largely abolished the inhibitory effects of penfluridol on TNFα-induced inflammatory cytokine production. Furthermore, penfluridol suppressed the differentiation of spleen naive CD4+T cells to TH1 and TH17 and inhibited M1 macrophage polarization.ConclusionThis study provides the rationale for the possible innovative use of penfluridol as a newly identified small-molecule drug for TNFα-driven diseases, such as inflammatory arthritis and colitis.
Highlights
Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine released by several cell types such as macrophages and monocytes, plays an important role inChen et al Arthritis Research & Therapy (2022) 24:27 golilmumab, infliximab) which have been approved for clinical use, and the most common application is to treat rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) [4]
Penfluridol is isolated as an anti‐NF‐κB activation drug Through first screening a FDA-approved small-molecule drug library containing 1046 drugs using NF-κBbla THP1, secondary confirmation by NF-κB luciferase reporter assay, and third in vivo verification in human TNFα transgenic (hTNF-TG)/ NF-κB luc mutant mice, we identified penfluridol as one of five drugs that could inhibit tumor necro‐ sis factor α (TNFα)-induced NF-κB activity [10]
Penfluridol inhibits TNFα‐induced NF‐κB activity in vitro To further verify the inhibitory effect of penfluridol on TNFα-stimulated NF-κB activation in vitro, we assessed the phosphorylation of several molecules in the NF-κB signaling pathway, translocation of p65, binding activity of NF-κB p65 to DNA, and mRNA expression and release levels of several inflammatory cytokines in Bone marrow-derived macrophages (BMDM) or Raw 264.7 cells
Summary
Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine released by several cell types such as macrophages and monocytes, plays an important role inChen et al Arthritis Research & Therapy (2022) 24:27 golilmumab, infliximab) which have been approved for clinical use, and the most common application is to treat RA and IBD [4]. Adverse effects of TNFi occur in 15% of patients and drug regimens are associated with high cost, approximately $40,000 per year for a patient [6,7,8]. Penfluridol, a first generation diphenylbutylpiperidine antipsychotic with a long half-life of 66 h, is a typical highly potent small-molecule drug used to treat chronic schizophrenia and related disorders [11,12,13,14], with treatment efficacy and risk of adverse events similar to chlorpromazine, a benchmark antipsychotic for schizophrenia. Penfluridol, isolated from an FDA-approved small-molecule drug library as an inhibitor of tumor necro‐ sis factor α (TNFα)-stimulated NF-κB activation, is clinically used to treat chronic schizophrenia and related disorders. This study is aimed to investigate the therapeutic effect of penfluridol on TNFα-stimulated inflammatory autoimmune diseases, inflammatory arthritis
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