title: Sex differences in the response to poly(ADP-ribose) polymerase-1 deletion and caspase inhibition after stroke.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Fudong
authors.initials: F
authors.lastname: Liu
authors.forename: Jesse
authors.initials: J
authors.lastname: Lang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Benashski
authors.forename: Matthew
authors.initials: M
authors.lastname: Siegel
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Louise D
authors.initials: LD
authors.lastname: McCullough
mesh_terms: D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D012727:Sex Characteristics; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology*
chemical_list: D061945:Caspase Inhibitors; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases