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-alpha, 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 mu g) 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-alpha and IL-6 were measured in plasma, and those of TNF-alpha 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-alpha by 75%. AN1297 and AN1284 (0.075 mg/kg) prevented the rise in TNF-alpha 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. (c) 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.