Biphasic modulation by nitric oxide of caspase activation due to malonate injection in rat striatum.
The present study examined caspase activation and its modulation by nitric oxide (NO) in a model of oxidative stress induced by injection of malonate (3 micromol), a mitochondrial toxin, into rat striatum. Caspase-3-like enzymatic activity was maximal 6 h after malonate while NO production evaluated by its metabolites nitrites and nitrates was increased at 3 h. The neuronal NO-synthase inhibitor 7-nitroindazole reduced malonate induced-NO production by 50% at 25 mg/kg and enhanced by 32% caspase activation. This result suggests that a moderate production of NO potentiates caspase activation, an effect counterbalanced by NO itself at higher concentrations. Accordingly, complete inhibition of NO production by 7-nitroindazole at 50 mg/kg did not modify malonate-induced caspase activity. Thus NO production by the neuronal isoform of NO-synthase is not the major event leading to caspase activation due to malonate. However, NO seems to have pro- and anti-caspase effects that neutralize each other.
Paucard
Alexia
A
Laboratoire de Pharmacologie, Université René Descartes, 4 avenue de l'Observatoire, 75006 Paris, France.
Palmier
Bruno
B
Croci
Nicole
N
Taillieu
Fanny
F
Plotkine
Michel
M
Margaill
Isabelle
I
D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D008314:Malonates / Q000008:administration & dosage*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley
D061945:Caspase Inhibitors; D007191:Indazoles; D008314:Malonates; D009569:Nitric Oxide; C030290:malonic acid; D020169:Caspases; C080122:7-nitroindazole