Limits...
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

TRO40303 reduces apoptosis in mice intoxicated with Jo2. (A) TRO40303 was administered p.o. to mice at 300 mg/kg in olive oil. Blood samples (n = 3 mice per time point) were taken at 1, 2, 4, 8, and 24 h after drug administration and quantification of TRO40303 in plasma samples was performed by LC-MS-MS to analyze the pharmacokinetic profile of the compound. (B) The dose of 125 μg/kg Jo2 antibody was administered i.p. to mice 4 h after TRO40303 treatment (p.o. dose of 300 mg/kg in olive oil compared to vehicle). ALAT activity was assayed in plasma 24 h postintoxication. Results are presented as mean ± SEM and statistical analysis was performed by t-test (**P < 0.01). (C) Western blot analysis of cleaved caspase 3, cleaved caspase 7, and cytochrome C on 60 μg of cytosolic liver extracts from mice treated as described in B with 125 μg/kg Jo2 ± 300 mg/kg TRO40303 p.o. compared to cytosolic liver extracts prepared from a control untreated mouse. Western blot actin levels were used as a loading control ensuring that the same amount of protein is loaded in each lane. p.o., per os.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492760&req=5

fig03: TRO40303 reduces apoptosis in mice intoxicated with Jo2. (A) TRO40303 was administered p.o. to mice at 300 mg/kg in olive oil. Blood samples (n = 3 mice per time point) were taken at 1, 2, 4, 8, and 24 h after drug administration and quantification of TRO40303 in plasma samples was performed by LC-MS-MS to analyze the pharmacokinetic profile of the compound. (B) The dose of 125 μg/kg Jo2 antibody was administered i.p. to mice 4 h after TRO40303 treatment (p.o. dose of 300 mg/kg in olive oil compared to vehicle). ALAT activity was assayed in plasma 24 h postintoxication. Results are presented as mean ± SEM and statistical analysis was performed by t-test (**P < 0.01). (C) Western blot analysis of cleaved caspase 3, cleaved caspase 7, and cytochrome C on 60 μg of cytosolic liver extracts from mice treated as described in B with 125 μg/kg Jo2 ± 300 mg/kg TRO40303 p.o. compared to cytosolic liver extracts prepared from a control untreated mouse. Western blot actin levels were used as a loading control ensuring that the same amount of protein is loaded in each lane. p.o., per os.

Mentions: In order to further investigate the mode of protection afforded by TRO40303 in the Fas-intoxicated mice, additional experiments were performed to evaluated TRO40303 efficacy when administered p.o. using the sublethal dose of Jo2 of 125 μg/kg. In these experiments, 300 mg/kg TRO40303 was administered 4 h before intoxication, as the plasma concentration at this time, is similar to what was found 2 h after administering 30 mg/kg i.p. (Fig.3A).


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)

TRO40303 reduces apoptosis in mice intoxicated with Jo2. (A) TRO40303 was administered p.o. to mice at 300 mg/kg in olive oil. Blood samples (n = 3 mice per time point) were taken at 1, 2, 4, 8, and 24 h after drug administration and quantification of TRO40303 in plasma samples was performed by LC-MS-MS to analyze the pharmacokinetic profile of the compound. (B) The dose of 125 μg/kg Jo2 antibody was administered i.p. to mice 4 h after TRO40303 treatment (p.o. dose of 300 mg/kg in olive oil compared to vehicle). ALAT activity was assayed in plasma 24 h postintoxication. Results are presented as mean ± SEM and statistical analysis was performed by t-test (**P < 0.01). (C) Western blot analysis of cleaved caspase 3, cleaved caspase 7, and cytochrome C on 60 μg of cytosolic liver extracts from mice treated as described in B with 125 μg/kg Jo2 ± 300 mg/kg TRO40303 p.o. compared to cytosolic liver extracts prepared from a control untreated mouse. Western blot actin levels were used as a loading control ensuring that the same amount of protein is loaded in each lane. p.o., per os.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: TRO40303 reduces apoptosis in mice intoxicated with Jo2. (A) TRO40303 was administered p.o. to mice at 300 mg/kg in olive oil. Blood samples (n = 3 mice per time point) were taken at 1, 2, 4, 8, and 24 h after drug administration and quantification of TRO40303 in plasma samples was performed by LC-MS-MS to analyze the pharmacokinetic profile of the compound. (B) The dose of 125 μg/kg Jo2 antibody was administered i.p. to mice 4 h after TRO40303 treatment (p.o. dose of 300 mg/kg in olive oil compared to vehicle). ALAT activity was assayed in plasma 24 h postintoxication. Results are presented as mean ± SEM and statistical analysis was performed by t-test (**P < 0.01). (C) Western blot analysis of cleaved caspase 3, cleaved caspase 7, and cytochrome C on 60 μg of cytosolic liver extracts from mice treated as described in B with 125 μg/kg Jo2 ± 300 mg/kg TRO40303 p.o. compared to cytosolic liver extracts prepared from a control untreated mouse. Western blot actin levels were used as a loading control ensuring that the same amount of protein is loaded in each lane. p.o., per os.
Mentions: In order to further investigate the mode of protection afforded by TRO40303 in the Fas-intoxicated mice, additional experiments were performed to evaluated TRO40303 efficacy when administered p.o. using the sublethal dose of Jo2 of 125 μg/kg. In these experiments, 300 mg/kg TRO40303 was administered 4 h before intoxication, as the plasma concentration at this time, is similar to what was found 2 h after administering 30 mg/kg i.p. (Fig.3A).

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