Involvement of oxidative stress in 3-nitropropionic acid neurotoxicity.
3-Nitroproprionic acid (3-NP) is a plant mycotoxin which produces selective striatal lesions in both experimental animals and in man. We previously found evidence that its neurotoxicity may be mediated by a secondary excitotoxic mechanism. In the present study we examined whether oxidative stress plays a role in the neurotoxicity of 3-NP in vivo. We examined whether the free radical spin traps alpha-phenyl-n-tert-butyl-nitrone (PBN), n-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN) or 5,5-dimethyl-1-pyrroline-n-oxide (DMPO) could attenuate the neurotoxicity of 3-NP. Striatal lesions produced by systemic administration of 3-NP were protected by pretreatment with DMPO, but the toxicity of 3-NP was increased by PBN or S-PBN pretreatment. The content of 3-NP in the plasma was increased by S-PBN, but not by DMPO consistent with an effect of S-PBN on 3-NP metabolism. Lesions produced by systemic administration of 3-NP increased the production of hydroxyl free radicals (OH) in the striatum as assessed by the conversion of salicylate to 2,3 and 2,5 dihydroxybenzoic acid (DHBA). These results provide direct evidence that free radicals play a substantial role in the neurotoxicity of 3-NP induced neuronal injury.
Schulz
J B
JB
Neurochemistry Laboratory, Massachusetts General Hospital, Boston, USA.
Henshaw
D R
DR
MacGarvey
U
U
Beal
M F
MF
D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000517:prevention & control; D009574:Nitro Compounds; D009589:Nitrogen Oxides / Q000494:pharmacology; D018384:Oxidative Stress; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels
D001557:Benzenesulfonates; D003497:Cyclic N-Oxides; D009574:Nitro Compounds; D009589:Nitrogen Oxides; D011422:Propionates; D013113:Spin Labels; C094272:N-tert-butyl-(2-sulfophenyl)nitrone; D017665:Hydroxyl Radical; C029217:phenyl-N-tert-butylnitrone; C017245:5,5-dimethyl-1-pyrroline-1-oxide; C015392:3-nitropropionic acid