Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor

D Chauvier; S Renolleau; S Holifanjaniaina; S Ankri; M Bezault; L Schwendimann; C Rousset; R Casimir; J Hoebeke; M Smirnova; G Debret; A-P Trichet; Y Carlsson; X Wang; E Bernard; M Hébert; J-M Rauzier; S Matecki; A Lacampagne; P Rustin; J Mariani; H Hagberg; P Gressens; C Charriaut-Marlangue; E Jacotot

doi:10.1038/cddis.2011.87

Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor

D Chauvier, S Renolleau, S Holifanjaniaina, S Ankri, M Bezault, L Schwendimann, C Rousset, R Casimir, J Hoebeke, M Smirnova, G Debret, A-P Trichet, Y Carlsson, X Wang, E Bernard, M Hébert, J-M Rauzier, S Matecki, A Lacampagne, P RustinJ Mariani, H Hagberg, P Gressens, C Charriaut-Marlangue, E Jacotot

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Abstract

Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia-ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns.

Original language	English
Article number	e203
Pages (from-to)	e203
Journal	Cell Death & Disease
Volume	2
Issue number	9
DOIs	https://doi.org/10.1038/cddis.2011.87
Publication status	Published - 1 Sept 2011

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Chauvier, D., Renolleau, S., Holifanjaniaina, S., Ankri, S., Bezault, M., Schwendimann, L., Rousset, C., Casimir, R., Hoebeke, J., Smirnova, M., Debret, G., Trichet, A.-P., Carlsson, Y., Wang, X., Bernard, E., Hébert, M., Rauzier, J.-M., Matecki, S., Lacampagne, A., ... Jacotot, E. (2011). Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor. Cell Death & Disease, 2(9), e203. Article e203. https://doi.org/10.1038/cddis.2011.87

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abstract = "Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia-ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns.",

author = "D Chauvier and S Renolleau and S Holifanjaniaina and S Ankri and M Bezault and L Schwendimann and C Rousset and R Casimir and J Hoebeke and M Smirnova and G Debret and A-P Trichet and Y Carlsson and X Wang and E Bernard and M H{\'e}bert and J-M Rauzier and S Matecki and A Lacampagne and P Rustin and J Mariani and H Hagberg and P Gressens and C Charriaut-Marlangue and E Jacotot",

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Chauvier, D, Renolleau, S, Holifanjaniaina, S, Ankri, S, Bezault, M, Schwendimann, L, Rousset, C, Casimir, R, Hoebeke, J, Smirnova, M, Debret, G, Trichet, A-P, Carlsson, Y, Wang, X, Bernard, E, Hébert, M, Rauzier, J-M, Matecki, S, Lacampagne, A, Rustin, P, Mariani, J, Hagberg, H , Gressens, P, Charriaut-Marlangue, C & Jacotot, E 2011, 'Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor', Cell Death & Disease, vol. 2, no. 9, e203, pp. e203. https://doi.org/10.1038/cddis.2011.87

TY - JOUR

T1 - Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor

AU - Chauvier, D

AU - Renolleau, S

AU - Holifanjaniaina, S

AU - Ankri, S

AU - Bezault, M

AU - Schwendimann, L

AU - Rousset, C

AU - Casimir, R

AU - Hoebeke, J

AU - Smirnova, M

AU - Debret, G

AU - Trichet, A-P

AU - Carlsson, Y

AU - Wang, X

AU - Bernard, E

AU - Hébert, M

AU - Rauzier, J-M

AU - Matecki, S

AU - Lacampagne, A

AU - Rustin, P

AU - Mariani, J

AU - Hagberg, H

AU - Gressens, P

AU - Charriaut-Marlangue, C

AU - Jacotot, E

PY - 2011/9/1

Y1 - 2011/9/1

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AB - Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia-ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns.

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DO - 10.1038/cddis.2011.87

M3 - Article

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VL - 2

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JO - Cell Death & Disease

JF - Cell Death & Disease

IS - 9

M1 - e203

ER -

Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor

Abstract

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