PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury

J Neurochem. 2004 Sep;90(5):1068-75. doi: 10.1111/j.1471-4159.2004.02547.x.

Abstract

Poly(ADP-ribose) polymerase-1 is over-activated in the adult brain in response to ischemia and contributes to neuronal death, but its role in perinatal brain injury remains uncertain. To address this issue, 7-day-old wild-type (wt) and PARP-1 gene deficient (parp+/- and parp-/-) Sv129/CD-1 hybrid mice were subjected to unilateral hypoxia-ischemia and histologic damage was assessed 10 days later by two evaluators. Poly(ADP-ribose) polymerase-1 knockout produced moderate but significant (p < 0.05) protection in the total group of animals, but analysis by sex revealed that males were strongly protected (p < 0.05) in contrast to females in which there was no significant effect. Separate experiments demonstrated that PARP-1 was activated over 1-24 h in both females and males after the insult in neonatal wt mice and rats using immnocytochemistry and western blotting for poly(ADP-ribose). Brain levels of NAD+ were also significantly reduced, but the decrease of NAD+ during the early post-hypoxia-ischemia (HI) phase was only seen in males. The results indicate that hypoxia-ischemia activates Poly(ADP-ribose) polymerase-1 in the neonatal brain and that the sex of the animal strongly influences its role in the pathogenesis of brain injury.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Blotting, Western / methods
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism
  • Brain Ischemia / prevention & control*
  • Cell Count / methods
  • Female
  • Functional Laterality / physiology
  • Immunohistochemistry / methods
  • Male
  • Mice
  • Mice, Knockout
  • Mortality
  • NAD / metabolism
  • Poly(ADP-ribose) Polymerases / deficiency*
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • Rabbits
  • Sex Factors
  • Time Factors

Substances

  • NAD
  • Poly(ADP-ribose) Polymerases