TRO40303, a mitochondrial‐targeted cytoprotective compound, provides protection in hepatitis models

Abstract

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.

Protective effect of sulfated polysaccharide isolated fromUlva fasciataagainst galactosamine-induced liver injury in rats

“…Acute liver injury is a major public health problem worldwide that arises from various etiologies including viral hepatitis, drug or alcohol‐induced injury, as well as hepatic ischemia‐reperfusion injury (Schaller et al, ). d ‐Galactosamine (GalN) induces liver cell injury in rodents, which closely resembles human acute viral hepatitis in its morphological and functional features (Keppler & Decker, ).…”

Administration of the Mitochondrial Permeability Transition Pore Inhibitor, TRO40303, prior to Primary Percutaneous Coronary Intervention, Does Not Affect the Levels of Pro-Inflammatory Cytokines or Acute-Phase Proteins

“…A sublethal dose of TRO40303 has also been tested in an experimental hepatitis model where the authors showed a significant reduction in mortality [45]. The dose chosen in the MITOCARE trial might have been inadequate to achieve the optimal delaying of the mPTP opening and higher dosage could be essential in order to reduce oxidative stress in the ischemic reperfused cardiomyocytes more efficiently.…”

“…The opening of mPTP can be modulated directly by different pharmacologic agents, for example, cyclosporine or indirectly for instance by preconditioning [44]. In vitro studies have shown that the blockage of the mPTP in ischemic cardiomyocytes resulted in reduced levels of oxidative stress [45]. So far, 5 randomized trials have investigated the effect of cyclosporine on reperfusion injury.…”

A narrative review of acute pancreatitis and its diagnosis, pathogenetic mechanism, and management

“…As a MPTP inhibitor, TRO40303 can effectively maintain the cell membrane potential and prevent necrosis in animal models of alcoholic pancreatitis and human acinar cells (39). TRO40303 is effective and well tolerated in the treatment of acute myocardial infarction and hepatitis and may be an effective way to treat AP (40,41). A multicenter clinical trial is underway to evaluate the effectiveness of high-calorie parenteral nutrition (PN) to maintain sufficient ATP consumption during AP (42).…”