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Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection.
J Cereb Blood Flow Metab. 2005 Apr; 25(4):502-12.JC

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+Show Affiliations

Department of Neurology, University of Connecticut Health Center, Farmington, Connecticut 06030-1840, USA. lmccullough@uchc.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15689952

Citation

McCullough, Louise D., et al. "Ischemic Nitric Oxide and Poly (ADP-ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 25, no. 4, 2005, pp. 502-12.
McCullough LD, Zeng Z, Blizzard KK, et al. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab. 2005;25(4):502-12.
McCullough, L. D., Zeng, Z., Blizzard, K. K., Debchoudhury, I., & Hurn, P. D. (2005). Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 25(4), 502-12.
McCullough LD, et al. Ischemic Nitric Oxide and Poly (ADP-ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection. J Cereb Blood Flow Metab. 2005;25(4):502-12. PubMed PMID: 15689952.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. AU - McCullough,Louise D, AU - Zeng,Zhiyuan, AU - Blizzard,Kathleen K, AU - Debchoudhury,Indira, AU - Hurn,Patricia D, PY - 2005/2/4/pubmed PY - 2005/5/4/medline PY - 2005/2/4/entrez SP - 502 EP - 12 JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JO - J Cereb Blood Flow Metab VL - 25 IS - 4 N2 - 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. SN - 0271-678X UR - https://www.unboundmedicine.com/medline/citation/15689952/Ischemic_nitric_oxide_and_poly__ADP_ribose__polymerase_1_in_cerebral_ischemia:_male_toxicity_female_protection_ L2 - https://journals.sagepub.com/doi/10.1038/sj.jcbfm.9600059?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -