PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury.
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.
Perinatal Center, Sahlgrenska University Hospital, Göteborg, Sweden. Henrik.Hagberg@obgyn.gu.se
Henrik
H
Hagberg
Mary Ann
MA
Wilson
Hiroko
H
Matsushita
Changlian
C
Zhu
Mary
M
Lange
Malin
M
Gustavsson
Marc F
MF
Poitras
Ted M
TM
Dawson
Valina L
VL
Dawson
Frances
F
Northington
Michael V
MV
Johnston
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002452:Cell Count / Q000379:methods; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009026:Mortality; D009243:NAD / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D012737:Sex Factors; D013997:Time Factors
D009243:NAD; D011065:Poly(ADP-ribose) Polymerases