A tetrahydroisoquinoline alkaloid THI-28 reduces LPS-induced HMGB1 and diminishes organ injury in septic mice through p38 and PI3K/Nrf2/HO-1 signals

We investigated whether THI-28 [1-4-(hydroxyphenylethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] inhibits release of high mobility group box 1 (HMGB1), a late phase cytokine of sepsis, in lipopolysaccharide (LPS)-stimulated RAW264.7 cells through home oxygenase (HO)-1 induction so that it shows beneficial effects in the cecal ligation and puncture (CLP)-induced septic mouse model. Silencing of target genes (HO-1, Nrf-2) or pharmacological signal inhibitors was exploited to investigate the HO-1 induction by THI-28. The dependency of HO-1 by THI-28 on survival rate and circulating HMGB1 level was tested in CLP-induced septic mice. Results showed that a time- and concentration-dependent HO-1 induction by THI-28 was significantly reduced by transfection with siNrf2 RNA. The reduction of iNOS/NO and HMGB1 expression by THI-28 was significantly reversed by silencing HO-1 RNA or treatment with SB203580, a p38 MAPK inhibitor, or LY294002, a PI3K inhibitor in LPS-activated cells. Decreasing p-I kappa B alpha by THI-28 resulted in inhibition of NF-kappa B activity which was reversed by silencing HO-1 RNA in LPS-activated cells. Most importantly, increased survival and reduction of liver and kidney injury and circulating HMGB1 levels by THI-28 in CLP-mice were reversed by ZnPPIX, HO-1 inhibitor. Taken together, these findings suggest that the novel compound THI-28 induces the expression of HO-1 by activating the PI3K and p38 MAPK pathways and suppressed HMGB1 and iNOS production in LPS-treated macrophages and septic mice, which may be useful in treating organ injury due to sepsis. (C) 2013 Elsevier B.V. All rights reserved.