Caspase-3 deficiency during development increases vulnerability to hypoxic-ischemic injury through caspase-3-independent pathways.
Neonatal hypoxia-ischemia (H-I) is a common cause of perinatal morbidity and mortality leading to prominent activation of caspase-3 in the brain. Previous studies have shown that acute inhibition of caspase-3 can protect against neonatal H-I in rats. In this study, we investigated brain injury following neonatal H-I in mice deficient in caspase-3. Wild-type, caspase-3+/- and caspase-3-/- mice underwent unilateral carotid ligation at postnatal day (P) 7, followed by 45 min of exposure to 8% oxygen. Surprisingly, tissue loss at P14 was significantly higher in caspase-3-/- mice when compared to wild-type littermates. As in rats, we found that acute inhibition of caspase-3 in mice leads to decrease in tissue loss at P14. There was no difference in nuclear morphology, DNA laddering or calpain activation between caspase-3-/-caspase-3+/- and wild-type mice subjected to H-I, and there was no evidence for compensatory activation of other caspases in caspase-3-/- mice. Also, all genotypes showed evidence of mitochondrial dysfunction after H-I, suggesting that this is a critical point in regulation of neuronal cell death following neonatal H-I. Our results suggest that long-term inhibition of caspase-3 during development, unlike acute inhibition, leads to upregulation of caspase-3-independent cell death pathways and increases the vulnerability of the developing brain to neonatal H-I injury.
West
Tim
T
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Atzeva
Madeliene
M
Holtzman
David M
DM
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001921:Brain / Q000254:growth & development* / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000172:deficiency* / Q000235:genetics; D002467:Cell Nucleus / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D051381:Rats
C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases