title: Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection.
abstract: It is well established that tissue damage and functional outcome after experimental or clinical stroke are shaped by biologic sex. We investigated the novel hypothesis that ischemic cell death from neuronally derived nitric oxide (NO) or poly-ADP ribose polymerase (PARP-1) activation is sexually dimorphic and that interruption of these molecular death pathways benefits only the male brain. Female neuronal nitric oxide synthase (nNOS) knockout (nNOS-/-) mice exhibited exacerbated histological injury after middle cerebral artery occlusion (MCAO) relative to wild-type (WT) females, unlike the protection observed in male nNOS-/- littermates. Similarly, treatment with the nNOS inhibitor (7-nitroindozole, 25 mg/kg) increased infarction in female C57Bl6 WT mice, but protected male mice. The mechanism for this sexually specific response is not mediated through changes in protein expression of endothelial NOS or inducible NOS, or differences in intraischemic cerebral blood flow. Unlike male PARP-1 knockouts (PARP1-/-), female PARP1-/- littermates sustained grossly increased ischemic damage relative to sex-matched WT mice. Treatment with a PARP inhibitor (PJ-34, 10 mg/kg) resulted in identical results. Loss of PARP-1 resulted in reversal of the neuroprotective activity by the female sex steroid, 17beta estradiol. These data suggest that the previously described cell death pathways involving NO and PARP ischemic neurotoxicity may be operant solely in male brain and that the integrity of nNO/PARP-1 signaling is paradoxically protective in the female.
authors.affiliation: Department of Neurology, University of Connecticut Health Center, Farmington, Connecticut 06030-1840, USA. lmccullough@uchc.edu
authors.forename: Louise D
authors.initials: LD
authors.lastname: McCullough
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zeng
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Blizzard
authors.forename: Indira
authors.initials: I
authors.lastname: Debchoudhury
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Hurn
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D052248:Nitric Oxide Synthase Type I; D010052:Ovariectomy; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009569:Nitric Oxide; D004958:Estradiol; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases