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

Schaller S, Michaud M, Latyszenok V, Robert F, Hocine M, Arnoux T, Gabriac M, Codoul H, Bourhane A, de Bellefois IC, Afxantidis J, Pruss RM - Pharmacol Res Perspect (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Trophos S. A., Luminy Biotech Entreprise Marseille, France.

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.

No MeSH data available.


Related in: MedlinePlus

Posttreatment with TRO40303 protects mice from Jo2 intoxication. The dose of 175, 200, and 250 μg/kg Jo2 antibody was administered i.p. to mice 1 h before TRO40303 treatment (i.p. dose 30 mg/kg) (A). The dose of 175 and 200 μg/kg Jo2 antibody was administered i.p. to mice 2 h before TRO40303 treatment (i.p. dose 30 mg/kg) (B). Mortality was assessed by counting the number of surviving animals 24 h after intoxication in comparison with vehicle (CES). Percent of death rescue in the TRO40303 group compared to the vehicle group is calculated at each dose and time and presented in the bar graphs. Statistical analysis was performed for each TRO40303 group compared to its vehicle group at each dose and time, using a Fisher test on final survival (number of surviving mice 24 h after intoxication) (*P < 0.05, ** P < 0.01). Animal numbers, survival per group is given in Table1. CES, cremophor EL/ethanol/saline.
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fig04: Posttreatment with TRO40303 protects mice from Jo2 intoxication. The dose of 175, 200, and 250 μg/kg Jo2 antibody was administered i.p. to mice 1 h before TRO40303 treatment (i.p. dose 30 mg/kg) (A). The dose of 175 and 200 μg/kg Jo2 antibody was administered i.p. to mice 2 h before TRO40303 treatment (i.p. dose 30 mg/kg) (B). Mortality was assessed by counting the number of surviving animals 24 h after intoxication in comparison with vehicle (CES). Percent of death rescue in the TRO40303 group compared to the vehicle group is calculated at each dose and time and presented in the bar graphs. Statistical analysis was performed for each TRO40303 group compared to its vehicle group at each dose and time, using a Fisher test on final survival (number of surviving mice 24 h after intoxication) (*P < 0.05, ** P < 0.01). Animal numbers, survival per group is given in Table1. CES, cremophor EL/ethanol/saline.

Mentions: Increasing doses of Jo2 antibody (175, 200, and 250 μg/kg) were given by i.p. to mice leading to increasing cell death from 37.5% to 75% and 92.5%, respectively in vehicle-treated mice. TRO40303 administered i.p. at the dose of 30 mg/kg 1 h post-Jo2 intoxication was able to significantly reduce mortality (Fig.4 and Table1). The dose of 10 mg/kg of TRO40303 was also able to slightly reduce mortality when doses of 200 and 250 μg/kg of Jo2 antibody were used, although the effect was not statistically significant (Table1). Further studying the effect of 30 mg/kg TRO40303 as a posttreatment 2 h after administering 175 or 200 μg/kg Jo2 antibody showed that delaying treatment further is no longer protective (Fig.4 and Table1).


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

Schaller S, Michaud M, Latyszenok V, Robert F, Hocine M, Arnoux T, Gabriac M, Codoul H, Bourhane A, de Bellefois IC, Afxantidis J, Pruss RM - Pharmacol Res Perspect (2015)

Posttreatment with TRO40303 protects mice from Jo2 intoxication. The dose of 175, 200, and 250 μg/kg Jo2 antibody was administered i.p. to mice 1 h before TRO40303 treatment (i.p. dose 30 mg/kg) (A). The dose of 175 and 200 μg/kg Jo2 antibody was administered i.p. to mice 2 h before TRO40303 treatment (i.p. dose 30 mg/kg) (B). Mortality was assessed by counting the number of surviving animals 24 h after intoxication in comparison with vehicle (CES). Percent of death rescue in the TRO40303 group compared to the vehicle group is calculated at each dose and time and presented in the bar graphs. Statistical analysis was performed for each TRO40303 group compared to its vehicle group at each dose and time, using a Fisher test on final survival (number of surviving mice 24 h after intoxication) (*P < 0.05, ** P < 0.01). Animal numbers, survival per group is given in Table1. CES, cremophor EL/ethanol/saline.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492760&req=5

fig04: Posttreatment with TRO40303 protects mice from Jo2 intoxication. The dose of 175, 200, and 250 μg/kg Jo2 antibody was administered i.p. to mice 1 h before TRO40303 treatment (i.p. dose 30 mg/kg) (A). The dose of 175 and 200 μg/kg Jo2 antibody was administered i.p. to mice 2 h before TRO40303 treatment (i.p. dose 30 mg/kg) (B). Mortality was assessed by counting the number of surviving animals 24 h after intoxication in comparison with vehicle (CES). Percent of death rescue in the TRO40303 group compared to the vehicle group is calculated at each dose and time and presented in the bar graphs. Statistical analysis was performed for each TRO40303 group compared to its vehicle group at each dose and time, using a Fisher test on final survival (number of surviving mice 24 h after intoxication) (*P < 0.05, ** P < 0.01). Animal numbers, survival per group is given in Table1. CES, cremophor EL/ethanol/saline.
Mentions: Increasing doses of Jo2 antibody (175, 200, and 250 μg/kg) were given by i.p. to mice leading to increasing cell death from 37.5% to 75% and 92.5%, respectively in vehicle-treated mice. TRO40303 administered i.p. at the dose of 30 mg/kg 1 h post-Jo2 intoxication was able to significantly reduce mortality (Fig.4 and Table1). The dose of 10 mg/kg of TRO40303 was also able to slightly reduce mortality when doses of 200 and 250 μg/kg of Jo2 antibody were used, although the effect was not statistically significant (Table1). Further studying the effect of 30 mg/kg TRO40303 as a posttreatment 2 h after administering 175 or 200 μg/kg Jo2 antibody showed that delaying treatment further is no longer protective (Fig.4 and Table1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Trophos S. A., Luminy Biotech Entreprise Marseille, France.

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.

No MeSH data available.


Related in: MedlinePlus