3-Nitropropionic acid neurotoxicity is attenuated in copper/zinc superoxide dismutase transgenic mice.
The mitochondrial toxin 3-nitropropionic acid (3-NP) produces selective striatal lesions in both experimental animals and humans. The pathogenesis of the lesions involves secondary excitotoxicity that may then lead to free radical generation. To test this further we examined the effects of 3-NP in both transgenic (Tg) mice that carry the complete sequence for the human copper/zinc superoxide dismutase (SOD) gene as well as non-Tg littermate controls. The Tg-SOD mice showed a pronounced attenuation of Nissl-stained striatal lesions compared with non-Tg mice. Systemic administration of 3-NP resulted in production of hydroxyl free radicals as assessed by the conversion of salicylate to 2,3- and 2,5-dihydroxybenzoic acid. This production was attenuated significantly in Tg-SOD mice. In a similar way, 3-NP produced significant increases in 3-nitrotyrosine/tyrosine, a marker for peroxynitrite-mediated damage, which were significantly attenuated in Tg-SOD mice. These results support that oxygen free radicals and peroxynitrite play an important role in the pathogenesis of 3-NP neurotoxicity.
Beal
M F
MF
Neurochemistry Laboratory, Massachusetts General Hospital, Boston 02114, USA.
Ferrante
R J
RJ
Henshaw
R
R
Matthews
R T
RT
Chan
P H
PH
Kowall
N W
NW
Epstein
C J
CJ
Schulz
J B
JB
D000818:Animals; D006801:Humans; D062385:Hydroxybenzoates / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics* / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology*; D009574:Nitro Compounds; D011422:Propionates / Q000633:toxicity*; D012016:Reference Values; D013482:Superoxide Dismutase / Q000235:genetics*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
D062385:Hydroxybenzoates; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D017665:Hydroxyl Radical; C002744:3-nitrotyrosine; D014443:Tyrosine; D013482:Superoxide Dismutase; C015392:3-nitropropionic acid