Anti-Inflammatory Indoline Derivatives Mitigate Liver Damage in a Mouse Model of Acute Liver Injury
2Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem
3Institute for Medical Research Israel Canada, The Hebrew University of Jerusalem, Jerusalem
Acute liver failure (ALF) is a severe life-threatening clinical syndrome caused by sudden and severe liver injury.1 The underlying pathological cause for ALF is the extensive necrosis and apoptosis of hepatocytes that can be induced by acute bacterial or viral infections, excessive alcohol intake, drug overdose, idiosyncratic drug reactions and toxins.2-4
Exposure of mice to D-galactosamine (GalN) and lipopolysaccharides (LPS) induces acute liver failure through elevation of the cytokine TNF-α, which causes liver damage resembling that in the human disease. The current study evaluated in this model the effect of novel indoline derivatives (Figure), which display anti-inflammatory and antioxidant effects in macrophages.
AN1284 is able to prevent lethality, apoptosis, cytokine production and oxidative stress in a mouse model of acute liver failure induced by GalN/LPS at extremely low doses of 0.075-0.75 mg/kg. This remarkable potency accords with its anti-inflammatory activity in isolated macrophages in the low nanomolar or picomolar range. Moreover, in almost all measures of liver damage, AN1284 is at least as, if not more effective than dexamethasone (3 mg/kg). Both indoline derivatives AN1284 and AN1297 produce their anti-apoptotic and anti-inflammatory effects by preventing the phosphorylation of MAPK p38 and nuclear translocation of the transcription factor, AP-1.
References
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- Khashab, et al., Gastroenterol. Rep. 2007, 9, 66-73
- Lee, et al., Liver Dis. 2008, 28, 142–52
- O’Grady, et al., Med. J, 2005, 81, 148–154
Acknowledgment – Supported by “The Ministry of Science, Technology and Space, Israel”
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