title: Prevention of neonatal oxygen-induced brain damage by reduction of intrinsic apoptosis.
abstract: Within the last decade, it became clear that oxygen contributes to the pathogenesis of neonatal brain damage, leading to neurocognitive impairment of prematurely born infants in later life. Recently, we have identified a critical role for receptor-mediated neuronal apoptosis in the immature rodent brain. However, the contribution of the intrinsic apoptotic pathway accompanied by activation of caspase-2 under hyperoxic conditions in the neonatal brain still remains elusive. Inhibition of caspases appears a promising strategy for neuroprotection. In order to assess the influence of specific caspases on the developing brain, we applied a recently developed pentapeptide-based group II caspase inhibitor (5-(2,6-difluoro-phenoxy)-3(R,S)-(2(S)-(2(S)-(3-methoxycarbonyl-2(S)-(3-methyl-2(S)-((quinoline-2-carbonyl)-amino)-butyrylamino)propionylamino)3-methylbutyrylamino)propionylamino)-4-oxo-pentanoic acid methyl ester; TRP601). Here, we report that elevated oxygen (hyperoxia) triggers a marked increase in active caspase-2 expression, resulting in an initiation of the intrinsic apoptotic pathway with upregulation of key proteins, namely, cytochrome c, apoptosis protease-activating factor-1, and the caspase-independent protein apoptosis-inducing factor, whereas BH3-interacting domain death agonist and the anti-apoptotic protein B-cell lymphoma-2 are downregulated. These results coincide with an upregulation of caspase-3 activity and marked neurodegeneration. However, single treatment with TRP601 at the beginning of hyperoxia reversed the detrimental effects in this model. Hyperoxia-mediated neurodegeneration is supported by intrinsic apoptosis, suggesting that the development of highly selective caspase inhibitors will represent a potential useful therapeutic strategy in prematurely born infants.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany. marco.sifringer@charite.de
authors.forename: M
authors.initials: M
authors.lastname: Sifringer
authors.forename: I
authors.initials: I
authors.lastname: Bendix
authors.forename: C
authors.initials: C
authors.lastname: Börner
authors.forename: S
authors.initials: S
authors.lastname: Endesfelder
authors.forename: C
authors.initials: C
authors.lastname: von Haefen
authors.forename: A
authors.initials: A
authors.lastname: Kalb
authors.forename: S
authors.initials: S
authors.lastname: Holifanjaniaina
authors.forename: S
authors.initials: S
authors.lastname: Prager
authors.forename: G W
authors.initials: GW
authors.lastname: Schlager
authors.forename: M
authors.initials: M
authors.lastname: Keller
authors.forename: E
authors.initials: E
authors.lastname: Jacotot
authors.forename: U
authors.initials: U
authors.lastname: Felderhoff-Mueser
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020208:Brain Injury, Chronic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism / Q000473:pathology; D007223:Infant; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D010100:Oxygen / Q000633:toxicity*; D047928:Premature Birth; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D053477:Apoptotic Protease-Activating Factor 1; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D061945:Caspase Inhibitors; D018696:Neuroprotective Agents; D009842:Oligopeptides; D011804:Quinolines; C568137:quinolin-2-carbonyl-VD(OMe)VAD(OMe)-CH2-O(2,6F2)Ph; D045304:Cytochromes c; C490360:CASP2 protein, human; D053143:Caspase 2; D053148:Caspase 3; D003546:Cysteine Endopeptidases; D010100:Oxygen