Involvement of superoxide in excitotoxicity and DNA fragmentation in striatal vulnerability in mice after treatment with the mitochondrial toxin, 3-nitropropionic acid.
Oxidative stress and excitotoxicity have been implicated in selective striatal vulnerability caused by the mitochondrial toxin, 3-nitropropionic acid (3-NP), which may simulate Huntington's disease in animals and humans. The detailed mechanism of the role of superoxide in striatal vulnerability induced by 3-NP is still unknown. The authors investigated oxidative cellular injury and DNA fragmentation after systemic 3-NP injection in wild-type (Wt) mice and mutant mice with a deficiency in manganese superoxide dismutase (MnSOD; Sod2 -/+). Furthermore, they investigated the effects of decortication after 3-NP treatment in Sod2 -/+ mice, and copper/zinc SOD (CuZnSOD) treatment in recently developed Sod2 -/+ mice that overexpress CuZnSOD (SOD1 +/- / Sod2 -/+ mice). Oxidized hydroethidine, 8-hydroxyguanosine immunoreactivity, and nitrotyrosine immunoreactivity were increased in the Sod2 -/+ mice compared with the Wt mice after 3-NP treatment (P < 0.001). Decortication completely abolished oxidative striatal damage after 3-NP treatment in the Sod2 -/+ mice. Increased CuZnSOD attenuated DNA fragmentation and striatal lesion volume after 3-NP treatment in the Sod2 -/+ mice (P < 0.001). These data suggest that production of superoxide may be a critical step to excitotoxicity and subsequent DNA fragmentation in selective striatal vulnerability after 3-NP treatment.
Kim
Gyung W
GW
Department of Neurosurgery, Stanford University School of Medicine, California 94305-5487, USA.
Chan
Pak H
PH
D000818:Animals; D002541:Cerebral Decortication; D003342:Corpus Striatum / Q000187:drug effects*; D004249:DNA Damage; D053938:DNA Fragmentation; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D009498:Neurotoxins / Q000633:toxicity; D009574:Nitro Compounds; D010084:Oxidation-Reduction; D010617:Phenanthridines / Q000737:chemistry; D011422:Propionates / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics; D013481:Superoxides / Q000032:analysis / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis; D000099156:Superoxide Dismutase 2
D009498:Neurotoxins; D009574:Nitro Compounds; D010617:Phenanthridines; D011422:Propionates; D013482:Superoxide Dismutase; D013481:Superoxides; D014443:Tyrosine; D000099156:Superoxide Dismutase 2; C002744:3-nitrotyrosine; C058428:hydroethidine; C015392:3-nitropropionic acid