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Sex differences in the response to poly(ADP-ribose) polymerase-1 deletion and caspase inhibition after stroke.

AbstractBACKGROUND AND PURPOSE:
Emerging data suggest that the molecular cell death pathways triggered by ischemic insults differ in the male and female brain. Cell death in males is initiated by poly(ADP-ribose) polymerase-1 (PARP-1) activation; however, manipulation of this pathway paradoxically increases ischemic damage in females. In contrast, females are exquisitely sensitive to caspase-mediated cell death. The effect of caspase inhibition in PARP-1 knockout mice was evaluated to determine if the detrimental effects of PARP deletion in females were secondary to increased caspase activation.
METHODS:
Focal stroke was induced by transient or permanent middle cerebral artery occlusion (MCAO) in wild-type (WT) and PARP-1(-/-) mice of both sexes. The pan-caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VD-OPh), was administered 90 minutes after middle cerebral artery occlusion. Infarct size and neurological sores were assessed. Separate cohorts were used for protein analysis for PAR, Apoptosis inducing factor (AIF), caspase-9, and caspase-3.
RESULTS:
WT mice of both sexes had increased nuclear AIF after stroke compared to PARP-1(-/-) mice. PARP-1(-/-) females had higher mitochondrial cytochrome C and activated caspase-9 and -3 levels than WT female mice. PARP-1(-/-) females also had an increase in stroke-induced cytosolic cytochrome C release compared with WT females, which was not seen in males. Q-VD-OPh decreased caspase-9 in both males and females but only led to reduction of infarct in females. PARP-1(-/-) males had smaller infarcts, whereas PARP-1(-/-) females had larger strokes compared with WT. Q-VD-OPh significantly decreased infarct in both WT and PARP-1(-/-) females in both transient and permanent MCAO models, but had no effect in males.
CONCLUSIONS:
Deletion of PARP-1 reduces infarct in males but exacerbates injury in females. PARP-1(-/-) females have enhanced caspase activation. The detrimental effects of PARP loss in females can be reversed with caspase inhibition.
AuthorsFudong Liu, Jesse Lang, Jun Li, Sharon E Benashski, Matthew Siegel, Yan Xu, Louise D McCullough
JournalStroke; a journal of cerebral circulation (Stroke) Vol. 42 Issue 4 Pg. 1090-6 (Apr 2011) ISSN: 1524-4628 [Electronic] United States
PMID21311064 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Caspase Inhibitors
  • Parp1 protein, mouse
  • Poly(ADP-ribose) Polymerases
  • Caspases
Topics
  • Animals
  • Caspase Inhibitors
  • Caspases (physiology)
  • Disease Models, Animal
  • Female
  • Gene Deletion
  • Infarction, Middle Cerebral Artery (drug therapy, enzymology, etiology)
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • Poly(ADP-ribose) Polymerases (deficiency, genetics, physiology)
  • Sex Characteristics
  • Stroke (complications, drug therapy, enzymology)

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