TRO 40303, a mitochondrial‐targeted cytoprotective compound, provides protection in hepatitis models

TRO 40303 is cytoprotective compound that was shown to reduce infarct size in preclinical models of myocardial infarction. It targets mitochondria, delays mitochondrial permeability transition pore ( mPTP ) opening and reduces oxidative stress in cardiomyocytes submitted to ischemia/reperfusion in vitro. Because the involvement of the mitochondria and the mPTP has been demonstrated in chronic as well as acute hepatitis, we investigated the potential of TRO 40303 to prevent hepatocyte injury. A first set of in vitro studies showed that TRO 40303 (from 0.3 to 3 μ mol/L) protected HepG2 cells and primary mouse embryonic hepatocytes ( PMEH ) from palmitate intoxication, a model mimicking steatohepatitis. In PMEH , TRO 40303 provided similar protection against cell death due to Jo2 anti‐Fas antibody intoxication. Further studies were then preformed in a mouse model of Fas‐induced fulminant hepatitis induced by injecting Jo2 anti‐Fas antibody. When mice received a sublethal dose of Jo2 at 125 μ g/kg, TRO 40303 pretreatment prevented liver enzyme elevation in plasma in parallel with a decrease in cytochrome C release from mitochondria and caspase 3 and 7 activation in hepatic tissue. When higher, lethal doses of Jo2 were administered, TRO 40303 (10 and 30 mg/kg) significantly reduced mortality by 65–90% when administered intraperitoneally (i.p.) 1 h before Jo2 injection, a time when TRO 40303 plasma concentrations reached their peak. TRO 40303 (30 mg/kg, i.p.) was also able to reduce mortality by 30–50% when administered 1 h postlethal Jo2 intoxication. These results suggest that TRO 40303 could be a promising new therapy for the treatment or prevention of hepatitis.