Melatonin and Trimetazidine in IGL-1 solution: new insights for fatty liver preservation.

Organ-donor shortage has led to the acceptance of steatotic livers for transplantation, despite of the higher risk of graft dysfunction or nonfunction. IGL-1 solution has been successfully used to preserve steatotic livers. We demonstrate, the synergic effects of melatonin (ML) at 100µM and trimetazidine (TMZ) at 10 -6 M when both were added to IGL-1 solution. Steatotic (obese [Ob]) livers from Zücker rats (n = 8) were preserved for 24 hours at 4°C in IGL- 1 solution with ML, TMZ and ML+ TMZ, respectively, and then 2h-perfused at 37°C. Transaminases and function (bile production, vascular resistance, hepatic clearance), nitric oxide (nitrite/nitrates & immunohistochemistry) and oxidative stress were measured and compared to UW solution. Mitochondrial damage (GLDH) was also evaluated. Steatotic livers preserved in IGL-1 solution enriched with ML (IGL-1+ML), TMZ (IGL-1 + TMZ) and ML+TMZ (IGL-1 + ML+TMZ) showed lower transaminases and higher bile production and increased hepatic clearance than IGL-1 solution-preserved livers. At 2h reperfusion, ALT levels in steatotic livers were (92.99 ± 8.65 UL) in IGL-1 solution vs (63.54UL ± 7.5, p<0,05) in IGL-1+ML and IGL-1+ML+TMZ (45.31± 2.94, p<0,05), respectively. Similar ASTpattern was obtained. Bile increased in IGL-1+ML+TMZ solution (13.05±0.13 µL/min/g) when compared to IGL-1+ML (9.3±0.82 µL/min/g, p<0.05) and IGL-1 (5.04±1.56 µL/min/g, p<0,05), respectively. This was substantiated by a signifi cant vascular resistance decrease likely induced by nitric oxide generation (eNOS activation and nitrites and nitrates levels). In addition, oxidative stress was also prevented. In conclusion, ML+TMZ to IGL-1 provided a better protection of steatotic livers against cold ischemia-reperfusion injury than IGL-1 alone. This beneficial effect is associated with the prevention of fatty liver microcirculatory alterations due to reperfusion injury.