Role of peroxynitrite and neuronal nitric oxide synthase in the activation of poly(ADP-ribose) synthetase in a murine model of cerebral ischemia-reperfusion.
Poly(ADP-ribose) synthetase (PARS) activation, a downstream event of nitric oxide (NO) neurotoxicity has been implicated in cerebral reperfusion injury. The aim of our study was to identify the trigger of PARS activation during stroke. Formation of poly(ADP-ribose) profoundly increased in the early phase of reperfusion. Poly(ADP-ribose) formation was attenuated in mice deficient for neuronal NO synthase (nNOS). We next tested in glioma cells whether NO, or peroxynitrite (a cytotoxic oxidant formed from NO and superoxide) is the actual trigger of PARS activation. Peroxynitrite, but not various NO donors, activated PARS and suppressed cellular viability in a PARS-dependent fashion. Thus, nNOS is responsible for PARS activation in stroke. PARS activation, however, is not a direct result of NO production, but it occurs via peroxynitrite formation.
Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
M
M
Endres
G
G
Scott
S
S
Namura
A L
AL
Salzman
P L
PL
Huang
M A
MA
Moskowitz
C
C
Szabó
D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004789:Enzyme Activation; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I; D016877:Oxidants / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology
D009419:Nerve Tissue Proteins; D009566:Nitrates; D016877:Oxidants; C039642:peroxynitric acid; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D011065:Poly(ADP-ribose) Polymerases