Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury.

Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury. Research Abstract Details 

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Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury. Abstract Text:

BACKGROUND AND PURPOSE: Overactivation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) contributes to ischemic brain injury. Because PARP upregulates proinflammatory genes, we investigated whether inducible nitric oxide synthase (iNOS), a gene involved in the deleterious effects of postischemic inflammation, participates in the mechanisms by which PARP activation contributes to cerebral ischemic injury. METHODS: The middle cerebral artery (MCA) was occluded in mice for 20 minutes using an intravascular filament, and injury volume was measured 72 hours later in Nissl-stained brain sections. mRNA expression was assessed in the postischemic brain by the quantitative "real-time" polymerase chain reaction. RESULTS: The PARP inhibitor PJ34 reduced infarct volume and attenuated postischemic iNOS mRNA upregulation by 72%. To determine whether iNOS contributes to the toxicity of PARP, the iNOS inhibitor aminoguanidine was co-administered with PARP inhibitors. Unexpectedly, co-administration of PARP and iNOS inhibitors, or treatment of iNOS-null mice with PARP inhibitors, abrogated the protective effect afforded by iNOS or PARP inhibition alone. The loss of neuroprotection was associated with upregulation of the inflammatory genes iNOS, intercellular adhesion molecule-1, and gp91(phox). CONCLUSIONS: The results suggest that iNOS expression contributes to the deleterious effects exerted by PARP activation in cerebral ischemia. However, iNOS activity is required for the protective effect of PARP inhibition and, conversely, PARP activity must be present for iNOS inhibition to be effective. The findings unveil a previously unrecognized deleterious interaction between iNOS and PARP that is relevant to the development of combination therapies for ischemic stroke.

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Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Stroke; a journal of cerebral circulation

VOLUME: 35

Page Numbers: 2896-901

Journal Abbreviation: Stroke

ISSN: 1524-4628

DAY: 28

MONTH: 10

YEAR: 2004

Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury. Information

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LANGUAGE: eng

NlmUniqueID: 235266

Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury. Keywords Mesh Terms:

KEYWORDS: Up-Regulation

MESH TERMS: analysis

Chemical & Substance for Abstract: Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury. Information

Substance Name: Poly(ADP-ribose) Polymerases

Registry Number: EC 2.4.2.30

Grant and Affiliation Information for Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury.

AFFILIATION: Department of Pharmacology, College of Medicine, Ewha Women's University, Seoul, Republic of Korea.

Country: United States

AGENCY: United States NINDS

GRANT: NS35806

ACRONYM: NS

MEDLINETA: Stroke

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