BN82002 alleviated tissue damage of septic mice by reducing inflammatory response through inhibiting AKT2/NF-κB...

BN82002 is well-known as an inhibitor of the CDC25 phosphatase. However, it was recently reported that BN82002 also selectively suppressed AKT2 and reduced inflammatory responses in lipopolysaccharide (LPS)-stimulated macrophage-like RAW264.7 cells. Therefore, in this study, we evaluated the alleviating efficacy of BN82002 in sepsis in vivo. BN82002 (50 μM) suppressed the mRNA levels of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in LPS-treated peritoneal macrophages without cytotoxicity. The septic in vivo mouse model was established on the basis of the endotoxin model using poly(I:C) (10 mg/kg) and LPS (54 mg/kg). In histological analysis, peritoneal injection of BN82002 (20 mg/kg) significantly reduced lung, kidney, and liver damage. Lung edema and serum alanine transaminase (ALT), aspartate transaminase (AST), TNF-α, IL-1β, and nitric oxide (NO) levels also were decreased by BN82002 (20 mg/kg). In addition, BN82002 (20 mg/kg) suppressed the mRNA levels of TNF-α in lung and liver tissues. Gene expression levels of IL-1β and IL-6 were decreased in lung, kidney, and liver in the BN82002 (20 mg/kg) group. Furthermore, p-AKT2 and p-IκBα levels were reduced by BN82002 (20 mg/kg). Finally, all septic mice died 7 days after poly(I:C)/LPS-injection, whereas 4 mice in the BN82002 (20 mg/kg) group, survived strongly suggesting that BN82002 reduces sepsis mortality. In conclusion, we verified that pre-treatment with BN82002 protects against tissue damage and increases survival by inhibiting AKT2-NF-κB signaling in septic mice. These results suggest that BN82002 could be utilized in the treatment of sepsis.