TRO40303 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
TRO40303 to prevent hepatocyte injury. A first set of in vitro studies showed that
TRO40303 (from 0.3 to 3 μmol/L) protected HepG2 cells and primary mouse embryonic hepatocytes (PMEH) from
palmitate intoxication, a model mimicking
steatohepatitis. In PMEH,
TRO40303 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 μg/kg,
TRO40303 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,
TRO40303 (10 and 30 mg/kg) significantly reduced mortality by 65-90% when administered intraperitoneally (i.p.) 1 h before Jo2 injection, a time when
TRO40303 plasma concentrations reached their peak.
TRO40303 (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
TRO40303 could be a promising new
therapy for the treatment or prevention of
hepatitis.