1. 3-Aminobenzamide Prevents Concanavalin A-Induced Acute Hepatitis by an Anti-inflammatory and Anti-oxidative Mechanism
- Author
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Dolev Katz, Rajendar Kandhikonda, Orna Ernst, Roy Weinstain, Olga Bernadsky, Anna Lilja, Iain D. C. Fraser, Hussein Aeed, Joram Wardi, Iris Ben-Dror, Idan Ben-Nachum, Sebastian Katz, Tsaffrir Zor, Alexander Biro, and Yona Avni
- Subjects
0301 basic medicine ,Lipopolysaccharide ,Physiology ,medicine.medical_treatment ,Anti-Inflammatory Agents ,Nitric Oxide Synthase Type II ,Inflammation ,Pharmacology ,Poly(ADP-ribose) Polymerase Inhibitors ,medicine.disease_cause ,Antioxidants ,Hepatitis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,In vivo ,medicine ,Concanavalin A ,Animals ,Cells, Cultured ,Liver injury ,biology ,Tumor Necrosis Factor-alpha ,Macrophages ,Gastroenterology ,NF-kappa B ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Cytokine ,Treatment Outcome ,chemistry ,Acute Disease ,Benzamides ,biology.protein ,Tumor necrosis factor alpha ,medicine.symptom ,Mitogens ,Oxidative stress - Abstract
Concanavalin A is known to activate T cells and to cause liver injury and hepatitis, mediated in part by secretion of TNFα from macrophages. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been shown to prevent tissue damage in various animal models of inflammation. The objectives of this study were to evaluate the efficacy and mechanism of the PARP-1 inhibitor 3-aminobenzamide (3-AB) in preventing concanavalin A-induced liver damage. We tested the in vivo effects of 3-AB on concanavalin A-treated mice, its effects on lipopolysaccharide (LPS)-stimulated macrophages in culture, and its ability to act as a scavenger in in vitro assays. 3-AB markedly reduced inflammation, oxidative stress, and liver tissue damage in concanavalin A-treated mice. In LPS-stimulated RAW264.7 macrophages, 3-AB inhibited NFκB transcriptional activity and subsequent expression of TNFα and iNOS and blocked NO production. In vitro, 3-AB acted as a hydrogen peroxide scavenger. The ROS scavenger N-acetylcysteine (NAC) and the ROS formation inhibitor diphenyleneiodonium (DPI) also inhibited TNFα expression in stimulated macrophages, but unlike 3-AB, NAC and DPI were unable to abolish NFκB activity. PARP-1 knockout failed to affect NFκB and TNFα suppression by 3-AB in stimulated macrophages. Our results suggest that 3-AB has a therapeutic effect on concanavalin A-induced liver injury by inhibiting expression of the key pro-inflammatory cytokine TNFα, via PARP-1-independent NFκB suppression and via an NFκB-independent anti-oxidative mechanism.
- Published
- 2017