Abstract
Fetal asphyctic preconditioning, induced by a brief episode of experimental hypoxia-ischemia, offers neuroprotection to a subsequent more severe asphyctic insult at birth. Extensive cell stress and apoptosis are important contributing factors of damage in the asphyctic neonatal brain. Because ceramide acts as a second messenger for multiple apoptotic stimuli, including hypoxia/ischemia, we sought to investigate the possible involvement of the ceramide pathway in endogenous neuroprotection induced by fetal asphyctic preconditioning. Global fetal asphyxia was induced in rats by clamping both uterine and ovarian vasculature for 30 min. Fetal asphyxia resulted in acute changes in brain ceramide/sphingomyelin metabolic enzymes, ceramide synthase 1, 2, and 5, acid sphingomyelinase, sphingosine-1-phosphate phosphatase, and the ceramide transporter. This observation correlated with an increase in neuronal apoptosis and in astrocyte number. After birth, ceramide and sphingomyelin levels remained high in fetal asphyxia brains, suggesting that a long-term regulation of the ceramide pathway may be involved in the mechanism of tolerance to a subsequent, otherwise lethal, asphyctic event.
Highlights
Fetal asphyctic preconditioning, induced by a brief episode of experimental hypoxia-ischemia, offers neuroprotection to a subsequent more severe asphyctic insult at birth
Because ceramide is an important regulator of cell growth and apoptosis [22], we studied the acute effect of fetal asphyxia in the ceramide signaling pathway (Fig. 2) at several prenatal and postnatal time points (Fig. 1B)
To investigate whether ceramide metabolism genes change at 6 and 12 h after fetal asphyctic preconditioning, we examined by RT-PCR the expression of several enzymes involved in ceramide metabolism: Lass1 to Lass6, sphingomyelin synthase 1 and 2 (SMS1-2), acid sphingomyelinase (aSMase), nSMase1-2, sphingosine kinase 1 (SphK1), and sphingosine-1-phosphate phosphatase (Sph1PP)
Summary
Fetal asphyctic preconditioning, induced by a brief episode of experimental hypoxia-ischemia, offers neuroprotection to a subsequent more severe asphyctic insult at birth. Because ceramide acts as a second messenger for multiple apoptotic stimuli, including hypoxia/ischemia, we sought to investigate the possible involvement of the ceramide pathway in endogenous neuroprotection induced by fetal asphyctic preconditioning. Fetal asphyxia resulted in acute changes in brain ceramide/sphingomyelin metabolic enzymes, ceramide synthase 1, 2, and 5, acid sphingomyelinase, sphingosine-1phosphate phosphatase, and the ceramide transporter. This observation correlated with an increase in neuronal apoptosis and in astrocyte number. Fetal asphyxia induces acute and persisting changes in the ceramide metabolism in rat brain. We aim to investigate acute changes occurring in the sphingomyelin/ceramide pathway after a sublethal fetal asphyctic insult to identify molecules important in brain tolerance. Better understanding of these mechanisms may allow the development of new neuroprotective therapies
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