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.
Highlights
Accumulating data suggest that apoptotic mechanisms have a more prominent role in the evolution of ischemic brain injury in neonatal rodents[9,10,11] and humans[12] than in adult brain ischemia,[13,14] and that apoptosis involves the mitochondrial release of cytochrome c11 and apoptosis-inducing factor (AIF),[11,15,16] which activate caspase-dependent[10,16] and -independent execution pathways,[13,16] respectively
We previously showed that the pancaspase inhibitor quinolyl-carbonyl-Val-Asp-difluorophenoxymethylketone (Q-VD-OPh) has enhanced in vitro and in vivo pharmacological properties,[33] together with potent neuroprotective effects in neonatal brain injury experimental models.[10,16,34]
Using the mitochondria isolated from neonatal brain, we found that a mixture containing rCasp[2] and full-length Bid induce TRP601sensitive cytochrome c release, correlating with Casp2induced Bid cleavage (Supplementary Figure S4)
Summary
Ischemic brain injury in the developing brain involves several factors such as excitotoxicity, oxidative stress, and inflammation, which accelerate cell death through either apoptosis or necrosis, depending on the region of the brain affected and on the severity of the insult.[7,8] Accumulating data suggest that apoptotic mechanisms have a more prominent role in the evolution of ischemic brain injury in neonatal rodents[9,10,11] and humans[12] than in adult brain ischemia,[13,14] and that apoptosis involves the mitochondrial release of cytochrome c11 and apoptosis-inducing factor (AIF),[11,15,16] which activate caspase-dependent[10,16] and -independent execution pathways,[13,16] respectively. On the basis of the optimal four-amino-acid sequence to the left of the cleavage site, caspases may be classified into three groups: group I contains caspase-1, -4, and -5 (optimal tetrapeptide: WEHD), group II contains caspase-2 (Casp2), -3 Both pancaspase inhibition and Casp3-selective inhibition have been reported to be neuroprotective in various rodent models of neonatal brain injury,[13,23,24] opening the possibility for pharmacological intervention.[6] lack of protection with caspase inhibitors was reported,[25,26] possibly reflecting differences between experimental models or settings (e.g., the age of animals26), specific in vivo properties of the used inhibitors (e.g., brain penetration27), and/or a shift to caspase-independent cell death pathways (e.g., AIF, autophagic death, necroptosis)
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