Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor
Chauvier et al. Cell Death and Disease (2011) (Impact Factor 8.1)
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.Ne vous souciez pas d’avoir l’air professionnel. Soyez vous-même. Il y a plus de 1,5 milliard de sites web, mais c’est votre histoire qui vous différenciera. Si, en relisant les mots, vous n’entendez pas votre propre voix dans votre tête, c’est le signe que vous avez encore du chemin à parcourir.
D Chauvier1,2, S Renolleau3,4,5, S Holifanjaniaina6,7, S Ankri1,2, M Bezault1,2, L Schwendimann6,7, C Rousset8,9, R Casimir1,2,10, J Hoebeke10, M Smirnova1,2, G Debret11,12, A-P Trichet2, Y Carlsson9,13, X Wang9, E Bernard2, M He´ bert2, J-M Rauzier14,15, S Matecki16,17, A Lacampagne15,17, P Rustin6,7, J Mariani3,4,18, H Hagberg8,9,13, P Gressens6,7,8, C Charriaut-Marlangue3,4 and E Jacotot*,1,2,6,7,8
1 Theraptosis Research Laboratory, Theraptosis SA, Pasteur BioTop, Institut Pasteur, Paris 75015, France; 2 Theraptosis R&D Laboratories, Theraptosis SA, Biocitech Technology Park, Romainville 93230, France; 3CNRS, UMR 7102 NPA, Paris 75005, France; 4Pierre and Marie Curie University Paris 6, UMR 7102 NPA, Paris 75005, France; 5Service de Reanimation Néonatale et Pediatrique, Hopital Armand Trousseau - APHP, Paris 75012, France; 6 Inserm, U676, Paris 75019, France; 7 Universite Paris Diderot, UMR 676, Paris 75019, France; 8 Centre for the Developing Brain, Institute of Reproductive and Developmental Biology, Imperial College London,Hammersmith Hospital, London W12 0NN, UK; 9 Department of Physiology, Perinatal Center, Sahlgrenska Academy, Go¨teborg University, Gothenburg 40530, Sweden;10 CNRS UPR 9021, Institut de Biologie Moleculaire et Cellulaire, Strasbourg 67084, France; 11 Laboratoire de Physique Theorique de la Matiere Condensee, CNRS UMR 7600, Paris 75005, France; 12 Pierre and Marie Curie University Paris 6 UMR 7600 LPTMC, Paris 75005, France; 13 Department of Obstetrics and Gynaecology, Sahlgrenska University Hospital, Gothenburg 41345, Sweden; 14 CHU de Nıˆmes, Nıˆmes 30000, France; 15 Inserm U1046, Montpellier 34925, France; 16 CHU de Montpellier, Montpellier 34925, France; 17 Universite´ Montpellier 1 et 2, Montpellier 34925, France and 18Hoˆ pital Charles Foix, UEF, Ivry-sur-Seine 94205, France
Cell Death and Disease (2011) 2, e203; doi:10.1038/cddis.2011.87; published online 1 September 2011. Subject Category: Neuroscience