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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

Pretreatment with TRO40303 protects mice from Jo2 intoxication. (A) TRO40303 was administered i.p. to mice at 30 mg/kg in CES. 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. Results are presented as mean ± SEM. (B) The dose of 125 μg/kg Jo2 antibody was administered i.p. to mice 1 h after TRO40303 treatment (i.p. doses of 3, 10 and 30 mg/kg in CES compared to vehicle). ALAT activity was assayed in plasma 24 h postintoxication. Results are presented as mean ± SEM and statistical analysis was performed by one-way analysis of variance (ANOVA) followed by Dunnett’s posttest compared to vehicle (**P < 0.01). (C) The dose of 250 μg/kg Jo2 antibody was administered i.p. to mice 1 h after TRO40303 treatment (i.p. doses of 10 and 30 mg/kg in CES compared to vehicle). Mortality was assessed by counting the number of surviving animals 24 h after intoxication. Results are presented in percent of initial mice surviving (n = 20 per TRO40303-treated group and n = 40 for vehicle) and statistical analysis was performed using Fisher test (P = 0.024 and P < 0.0001 for the 10 and 30 mg/kg doses, respectively). TRO40303 at 10 and 30 mg/kg improved viability of the mice by 47% and 90%, respectively. Results are presented as mean ± SEM for the vehicle group (mean of two experiments) and statistical analysis was performed by one-way ANOVA followed by Dunnett’s posttest compared to vehicle (*P < 0.05, ***P < 0.001). D) The dose of 200 μg/kg Jo2 antibody was administered i.v. to mice 1 h after TRO40303 treatment (30 mg/kg i.p. in CES compared to vehicle). The survival plot was established by video tracking for 24 h, starting just after intoxication. Results are presented in percent of initial mice surviving (n = 10 per group) and statistical analysis was performed using log-rank Mandel-Cox test (**P < 0.01). i.p., intraperitoneally; CES, cremophor EL/ethanol/saline; i.v., intravenous.
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fig02: Pretreatment with TRO40303 protects mice from Jo2 intoxication. (A) TRO40303 was administered i.p. to mice at 30 mg/kg in CES. 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. Results are presented as mean ± SEM. (B) The dose of 125 μg/kg Jo2 antibody was administered i.p. to mice 1 h after TRO40303 treatment (i.p. doses of 3, 10 and 30 mg/kg in CES compared to vehicle). ALAT activity was assayed in plasma 24 h postintoxication. Results are presented as mean ± SEM and statistical analysis was performed by one-way analysis of variance (ANOVA) followed by Dunnett’s posttest compared to vehicle (**P < 0.01). (C) The dose of 250 μg/kg Jo2 antibody was administered i.p. to mice 1 h after TRO40303 treatment (i.p. doses of 10 and 30 mg/kg in CES compared to vehicle). Mortality was assessed by counting the number of surviving animals 24 h after intoxication. Results are presented in percent of initial mice surviving (n = 20 per TRO40303-treated group and n = 40 for vehicle) and statistical analysis was performed using Fisher test (P = 0.024 and P < 0.0001 for the 10 and 30 mg/kg doses, respectively). TRO40303 at 10 and 30 mg/kg improved viability of the mice by 47% and 90%, respectively. Results are presented as mean ± SEM for the vehicle group (mean of two experiments) and statistical analysis was performed by one-way ANOVA followed by Dunnett’s posttest compared to vehicle (*P < 0.05, ***P < 0.001). D) The dose of 200 μg/kg Jo2 antibody was administered i.v. to mice 1 h after TRO40303 treatment (30 mg/kg i.p. in CES compared to vehicle). The survival plot was established by video tracking for 24 h, starting just after intoxication. Results are presented in percent of initial mice surviving (n = 10 per group) and statistical analysis was performed using log-rank Mandel-Cox test (**P < 0.01). i.p., intraperitoneally; CES, cremophor EL/ethanol/saline; i.v., intravenous.

Mentions: Since TRO40303 was able to protect PMEH from Fas-induced hepatotoxicity in vitro, we evaluated its effects in mice subjected to sublethal and lethal treatment with Jo2 anti-Fas antibody. TRO40303 has been developed to allow administration as a single i.v. bolus in acute, emergency indications (The MITOCARE Study Group 2012). For initial studies of the in vivo hepatoprotective potential of TRO40303, the compound was administered to mice via the i.p. route 1 h before Jo2 intoxication. The i.p. route was chosen for practical reasons in the mouse model, knowing that the pharmacokinetic profile of the compound (Fig.2A) was very similar to what was found with i.v. administration in previous studies (Le Lamer et al. 2014). In a second stage, TRO40303 was administered by i.v.


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)

Pretreatment with TRO40303 protects mice from Jo2 intoxication. (A) TRO40303 was administered i.p. to mice at 30 mg/kg in CES. 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. Results are presented as mean ± SEM. (B) The dose of 125 μg/kg Jo2 antibody was administered i.p. to mice 1 h after TRO40303 treatment (i.p. doses of 3, 10 and 30 mg/kg in CES compared to vehicle). ALAT activity was assayed in plasma 24 h postintoxication. Results are presented as mean ± SEM and statistical analysis was performed by one-way analysis of variance (ANOVA) followed by Dunnett’s posttest compared to vehicle (**P < 0.01). (C) The dose of 250 μg/kg Jo2 antibody was administered i.p. to mice 1 h after TRO40303 treatment (i.p. doses of 10 and 30 mg/kg in CES compared to vehicle). Mortality was assessed by counting the number of surviving animals 24 h after intoxication. Results are presented in percent of initial mice surviving (n = 20 per TRO40303-treated group and n = 40 for vehicle) and statistical analysis was performed using Fisher test (P = 0.024 and P < 0.0001 for the 10 and 30 mg/kg doses, respectively). TRO40303 at 10 and 30 mg/kg improved viability of the mice by 47% and 90%, respectively. Results are presented as mean ± SEM for the vehicle group (mean of two experiments) and statistical analysis was performed by one-way ANOVA followed by Dunnett’s posttest compared to vehicle (*P < 0.05, ***P < 0.001). D) The dose of 200 μg/kg Jo2 antibody was administered i.v. to mice 1 h after TRO40303 treatment (30 mg/kg i.p. in CES compared to vehicle). The survival plot was established by video tracking for 24 h, starting just after intoxication. Results are presented in percent of initial mice surviving (n = 10 per group) and statistical analysis was performed using log-rank Mandel-Cox test (**P < 0.01). i.p., intraperitoneally; CES, cremophor EL/ethanol/saline; i.v., intravenous.
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Related In: Results  -  Collection

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fig02: Pretreatment with TRO40303 protects mice from Jo2 intoxication. (A) TRO40303 was administered i.p. to mice at 30 mg/kg in CES. 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. Results are presented as mean ± SEM. (B) The dose of 125 μg/kg Jo2 antibody was administered i.p. to mice 1 h after TRO40303 treatment (i.p. doses of 3, 10 and 30 mg/kg in CES compared to vehicle). ALAT activity was assayed in plasma 24 h postintoxication. Results are presented as mean ± SEM and statistical analysis was performed by one-way analysis of variance (ANOVA) followed by Dunnett’s posttest compared to vehicle (**P < 0.01). (C) The dose of 250 μg/kg Jo2 antibody was administered i.p. to mice 1 h after TRO40303 treatment (i.p. doses of 10 and 30 mg/kg in CES compared to vehicle). Mortality was assessed by counting the number of surviving animals 24 h after intoxication. Results are presented in percent of initial mice surviving (n = 20 per TRO40303-treated group and n = 40 for vehicle) and statistical analysis was performed using Fisher test (P = 0.024 and P < 0.0001 for the 10 and 30 mg/kg doses, respectively). TRO40303 at 10 and 30 mg/kg improved viability of the mice by 47% and 90%, respectively. Results are presented as mean ± SEM for the vehicle group (mean of two experiments) and statistical analysis was performed by one-way ANOVA followed by Dunnett’s posttest compared to vehicle (*P < 0.05, ***P < 0.001). D) The dose of 200 μg/kg Jo2 antibody was administered i.v. to mice 1 h after TRO40303 treatment (30 mg/kg i.p. in CES compared to vehicle). The survival plot was established by video tracking for 24 h, starting just after intoxication. Results are presented in percent of initial mice surviving (n = 10 per group) and statistical analysis was performed using log-rank Mandel-Cox test (**P < 0.01). i.p., intraperitoneally; CES, cremophor EL/ethanol/saline; i.v., intravenous.
Mentions: Since TRO40303 was able to protect PMEH from Fas-induced hepatotoxicity in vitro, we evaluated its effects in mice subjected to sublethal and lethal treatment with Jo2 anti-Fas antibody. TRO40303 has been developed to allow administration as a single i.v. bolus in acute, emergency indications (The MITOCARE Study Group 2012). For initial studies of the in vivo hepatoprotective potential of TRO40303, the compound was administered to mice via the i.p. route 1 h before Jo2 intoxication. The i.p. route was chosen for practical reasons in the mouse model, knowing that the pharmacokinetic profile of the compound (Fig.2A) was very similar to what was found with i.v. administration in previous studies (Le Lamer et al. 2014). In a second stage, TRO40303 was administered by i.v.

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