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Published on: December 9, 2013
PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury
Henrik Hagberg1, Mary Ann Wilson, Hiroko Matsushita
1Perinatal Center, Sahlgrenska University Hospital, Göteborg, Sweden. Henrik.Hagberg@obgyn.gu.se
Insights
Poly(ADP-ribose) polymerase-1 (PARP-1) activation contributes to neonatal brain injury. PARP-1 deficiency protects males but not females, indicating sex-specific roles in hypoxia-ischemia brain damage.
Area of Science:
- Neuroscience
- Biochemistry
- Developmental Biology
Background:
- Poly(ADP-ribose) polymerase-1 (PARP-1) is implicated in adult brain injury.
- The role of PARP-1 in perinatal brain injury is not well understood.
- Neonatal hypoxia-ischemia (HI) is a significant cause of brain damage.
Purpose of the Study:
- To investigate the role of PARP-1 in neonatal brain injury following hypoxia-ischemia.
- To determine if PARP-1 deficiency affects the outcome of perinatal brain injury.
- To explore potential sex differences in PARP-1's contribution to brain injury.
Main Methods:
- Used a neonatal mouse model of unilateral hypoxia-ischemia.
- Compared wild-type and PARP-1 gene-deficient mice (parp+/- and parp-/-).
- Assessed histological brain damage and measured poly(ADP-ribose) and NAD+ levels.
Main Results:
- PARP-1 knockout provided moderate protection against brain injury.
- Male mice showed significant protection, while females did not.
- PARP-1 activation and NAD+ depletion occurred post-HI, with NAD+ decrease specific to males.
Conclusions:
- Hypoxia-ischemia activates PARP-1 in the neonatal brain.
- The sex of the animal significantly influences the role of PARP-1 in brain injury pathogenesis.
- PARP-1 inhibition may be a potential therapeutic strategy, but sex-specific effects need consideration.
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.
