Indoline derivatives mitigate liver damage in a mouse model of acute liver injury

Background exposure of mice to d-galactosamine (galn) and lipopolysaccharide (lps) induces acute liver failure through elevation of tnf-α,which causes liver damage resembling that in humans. the current study evaluated in this model the effect of two indoline derivatives,which have anti-inflammatory activity in macrophages. methods an1297 and an1284 (0.025–0.75 mg/kg) or dexamethasone (3 mg/kg),were injected subcutaneously,15 min before intraperitoneal injection of galn (800 mg) plus lps (50 μg) in male balb/c mice. after 6 h,their livers were evaluated histologically by staining with hematoxylin and eosin for tissue damage and by cleaved caspase 3 for apoptosis. activity of liver enzymes,alanine transaminase (alt) and aspartate aminotransferase (ast) and levels of tnf-α and il-6 were measured in plasma,and those of tnf-α and il-6,in the liver. results an1297 (0.075–0.75 mg/kg) and an1284 (0.25–0.75 mg/kg) maximally reduced alt by 51% and 80%,respectively. only an1284 (0.25 and 0.75 mg/kg) reduced ast by 41% and 48%. an1297 and an1284 (0.25 mg/kg) decreased activation of caspase 3 (a sign of apoptosis) by 80% and plasma tnf-α by 75%. an1297 and an1284 (0.075 mg/kg) prevented the rise in tnf-α and il-6 in the liver. an1284 (0.25 mg/kg) reduced mortality from 90% to 20% (p < 0.01) and an1297,to 60% (p = 0.121). both indoline derivatives inhibited the phosphorylation of mapk p38 and dna binding of the transcription factor,ap-1. conclusion while both compounds are highly potent anti-inflammatory agents,an1284 is more effective in mitigating the underlying causes of galn/lps-induced acute liver failure in mice. © 2017 institute of pharmacology,polish academy of sciences