Abstract | BACKGROUND 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: 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.
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Authors | Fudong Liu, Jesse Lang, Jun Li, Sharon E Benashski, Matthew Siegel, Yan Xu, Louise D McCullough |
Journal | Stroke
(Stroke)
Vol. 42
Issue 4
Pg. 1090-6
(Apr 2011)
ISSN: 1524-4628 [Electronic] United States |
PMID | 21311064
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Caspase Inhibitors
- Parp1 protein, mouse
- Poly (ADP-Ribose) Polymerase-1
- Poly(ADP-ribose) Polymerases
- Caspases
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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) Polymerase-1
- Poly(ADP-ribose) Polymerases
(deficiency, genetics, physiology)
- Sex Characteristics
- Stroke
(complications, drug therapy, enzymology)
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