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.

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

“…As previously shown by others and our group, hyperoxic conditions lead to an increase in neurodegeneration in the developing brain [18,20,26,27,28]. In conformity with our recently presented results [20], here we indicate that an exposure of infant rats to high oxygen conditions (FiO 2 80%) over 24 h caused an increasing neurodegeneration in the developing brain (fig.…”

“…As oxygen treatment cannot be completely avoided during neonatal intensive care, appropriate neuroprotective strategies are highly warranted, because hyperoxia leads to an increase in inflammatory mediators, oxidative stress and apoptotic cell death in the developing rodent brain as demonstrated previously [18,20,21,22,24,26]. …”

“…In recent years, clinical observations and experimental studies revealed that oxygen, which is widely used in neonatal intensive care to treat respiratory distress, triggers a disruption of intracellular redox homeostasis [16,17]. We previously demonstrated that this disturbance can lead to oxidative stress and inflammation, resulting in increased neuronal and oligodendroglial apoptotic cell death in the developing brain [18,19,20,21,22]. …”

Oxygenation of the Newborn: A Molecular Approach

“…Felderhoff-Mueser and coworkers [41,42] studied oxygen toxcicity in the preterm brain and found neurodegenerative changes and caspase activation. Also around term a relatively short exposure to hyperoxia may cause harm.…”

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“…Even a brief period of hyperoxia/hyperoxemia following a hypoxic insult promotes lipid peroxidation, enhances expression of inflammatory genes, and stimulates apoptosis in the CNS of newborn animals [14][15][16]. In the pre-cooling era, one study reported that severe hyeroxemia (PaO 2 >200 mmHg) was associated with increased odds of adverse outcome (OR 3.85) in newborns with intrapartum asphyxia [11].…”