期刊
CELL DEATH & DISEASE
卷 2, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2011.87
关键词
caspase inhibitor; perinatal brain damage; ischemia; neuroprotection
类别
资金
- French Ministry of Research [01H0476, 01H0477]
- Inserm
- Foundation Grace de Monaco
- Agence Nationale pour la Valorisation de la Recherche (ANVAR) [R0209330Q]
- Medical Research Council (MRC, UK) [P19381]
- University Paris 7
- Premup
- Medical Research Council (VR, Sweden) [2006-3396]
- ALF-LUA (Sweden) [ALFGBG2863]
- European Commission [LSHM-CT-2006-036534]
- Action Medical Research [1764] Funding Source: researchfish
- Medical Research Council [G0802853] Funding Source: researchfish
- MRC [G0802853] Funding Source: UKRI
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. Cell Death and Disease (2011) 2, e203; doi:10.1038/cddis.2011.87; published online 1 September 2011
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