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

D. Chauvier (1) , S. Renolleau (2, 3, 4) , S. Holifanjaniaina (5, 6) , S. Ankri (1) , M. Bezault (1) , L. Schwendimann (5, 6) , C. Rousset (7, 8) , R. Casimir (1, 9) , J. Hoebeke (9) , M. Smirnova (1) , G. Debret (10) , A.-P. Trichet (1) , Y. Carlsson (8, 11) , X. Wang (8) , E. Bernard (1) , M. Hébert (1) , J.-M. Rauzier (12) , Stefan Matecki (13, 14) , Alain Lacampagne (13) , P. Rustin (5, 6) , J. Mariani (2, 3, 15) , H. Hagberg (7, 8, 11) , P. Gressens (5, 6, 7) , C. Charriaut-Marlangue (2, 3) , E. Jacotot (1, 5, 6, 7)

1 Theraptosis S.A.
2 NPA - Neurobiologie des processus adaptatifs
3 UPMC - Université Pierre et Marie Curie - Paris 6
4 CHU Trousseau [APHP]
5 Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement
6 UPD7 - Université Paris Diderot - Paris 7
7 Centre for the developing brain
8 Department of Physiology
9 ICT - Immunologie et chimie thérapeutiques
10 LPTMC - Laboratoire de Physique Théorique de la Matière Condensée
11 Department of Obstetrics & Gynaecology
12 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
13 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
14 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
15 CHU Charles Foix [AP-HP]

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.

Mots clés: caspase inhibitor; perinatal brain damage; ischemia; neuroprotection

Domaines: Biologie moléculaire; Neurobiologie; Pharmacologie

D. Chauvier, S. Renolleau, S. Holifanjaniaina, S. Ankri, M. Bezault, et al.. Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor.. Cell Death and Disease, 2011, 2, pp.e203. ⟨10.1038/cddis.2011.87⟩. ⟨hal-00630609⟩