Abstract
Background and aims: Experimental studies show that oxygen, which is widely used in neonatal medicine for resuscitation and treatment of pulmonary hypertension, triggers a disruption of the maintenance of intracellular redox homeostasis. This disturbance can lead to oxidative stress and furthermore to neuronal apoptosis in the developing brain. The role of caspase-2 in apoptosis is poorly defined. Many in vitro studies of caspase-2 knockdown in cultured cells have implicated this caspase in cell death in response to different signaling pathways. To elucidate mechanisms of the caspase-2 inhibitor TRP601 and its mode of functioning in the developing brain in the context of hyperoxia, we investigated its impact on the levels of APAF-1, AIF, cytochrome c, caspase-9 and -3.
Methods: Six-day old rats were exposed together with their mothers to 80% oxygen in the presence or absence of the caspase-2 inhibitor TRP601 (1 mg/kg) and were sacrificed after 12 or 24 hrs of hyperoxia following treatment. Dissected brains were either examined histologically to visualize degenerating cells or were subjected to protein studies.
Results: Oxygen exposure triggered cell death at 12 to 24 hrs, which was attenuated by TRP601 treatment. Our protein studies demonstrated an upregulation of APAF-1, AIF, cytochrome c, caspase-9 and -3 in the cytosolic fraction of brain homogenates after hyperoxia, which reached control levels following TRP601 treatment.
Conclusion: These findings suggest a protective role for the caspase-2 inhibitor TRP601 in the prevention of neonatal oxygen-induced apoptotic brain damage.
Supported by the European Commission (Sixth Framework Program, contract no LSHM- CT-2006-036534).
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Sifringer, M., Boos, V., Börner, C. et al. 111 Impact of the Caspase-2 Inhibitor Trp601 on Apoptotic Signaling in the Developing Brain During Hyperoxia. Pediatr Res 68 (Suppl 1), 59 (2010). https://doi.org/10.1203/00006450-201011001-00111
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DOI: https://doi.org/10.1203/00006450-201011001-00111
