Efficacy and molecular mechanism of cell necrosis inhibitor TAK-632 in treatment of acute pancreatitis

  Objective  To investigate the protective effect of cell necrosis inhibitor TAK-632 for acute pancreatitis (AP) and its molecular mechanism.

  Methods  A total of 60 SD rats were randomly divided into control group, model group and TAK-632 group, with 20 rats in each group. The AP rat model was established. After 24 hours of modeling, rats in the control and model groups were injected with saline intraperitoneally, and rats in the TAK-632 group were injected with TAK-632 25 mg/kg intraperitoneally. After 72 hours of treatment, the survival rate, serum amylase activity, pancreatic pathological changes, the expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in peripheral blood, and the expressions of programmed necrosis protein receptor-interacting protein 3(RIP3) and mixed lineage kinase domain-like protein(MLKL) in pancreatic tissue were observed.

  Results  The survival rates of rats in the control group, model group, and TAK-632 group were 100.00%, 75.00% and 100.00%, respectively. Compared with the control group and TAK-632 group, the survival rate of the model group was significantly decreased (P < 0.05). Serum amylase activity and pathological scores of rats in the TAK-632 group were higher than those of the control group, but lower than those of the model group (P < 0.05). The levels of TNF-α, IL-1β and IL-6 in the peripheral blood of rats in the TAK-632 group were higher than those in the control group, but lower than those in the model group (P < 0.05). The levels of phosphorylated RIP3 and MLKL in the pancreatic tissue of rats in the TAK-632 group were higher than those in the control group, but lower than those in the model group (P < 0.05).

  Conclusion  TAK-632 can inhibit the release of inflammatory factors and slow the process of cell necrosis by inhibiting the phosphorylation of RIP3 and MLKL, thereby alleviating AP.