Deleterious activation of poly(ADP-ribose)polymerase-1 in brain after in vivo oxidative stress.
Oxidative stress has been shown to be implicated in the pathogenesis of central nervous system injuries such as cerebral ischemia and trauma, and chronic neurodegenerative diseases. In vitro studies show that oxidative stress, particularly peroxynitrite, could trigger DNA strand breaks, which lead to the activation of repairing enzymes including Poly(ADP-ribose) Polymerase-1 (PARP-1). As excessive activation of this enzyme induces cell death, we examined whether such a cascade also occurs in vivo in a model of oxidative stress in rat brain. For this purpose, the mitochondrial toxin malonate, which promotes free radical production, was infused into the left striatum of rats. Immunohistochemistry showed that 3-nitrotyrosine, an indicator of nitrosative stress, and poly(ADP-ribose), a marker of poly(ADP-ribose)polymerase-1 activation, were present as early as 1 h after malonate, and that they persisted for 24 h. The PARP inhibitor, 3-aminobenzamide, significantly reduced the lesion and inhibited PARP-1 activation induced by malonate. These results demonstrate that oxidative stress induced in vivo in the central nervous system leads to the activation of poly(ADP-ribose)polymerase-1, which contributes to neuronal cell death.
Besson
Valérie C
VC
Laboratoire de Pharmacologie de la Circulation Cérébrale, UPRES EA 2510, Université René Descartes, 4 avenue de l'Observatoire, F-75006 Paris, France.
Margaill
Isabelle
I
Plotkine
Michel
M
Marchand-Verrecchia
Catherine
C
D000818:Animals; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000201:enzymology*; D001927:Brain Diseases / Q000139:chemically induced / Q000201:enzymology*; D004789:Enzyme Activation; D007150:Immunohistochemistry; D008297:Male; D008314:Malonates; D018384:Oxidative Stress; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D001549:Benzamides; D008314:Malonates; D011064:Poly Adenosine Diphosphate Ribose; C002744:3-nitrotyrosine; D014443:Tyrosine; C025160:3-aminobenzamide; C030290:malonic acid; D011065:Poly(ADP-ribose) Polymerases