Paradoxical increase in 3-nitropropionic acid neurotoxicity by alpha-phenyl-tert-butyl-nitrone, a spin-trapping agent.
BACKGROUND
3-Nitropropionic acid (3-NP), a mitochondrial toxin, impairs cellular energy generation by inhibiting succinate dehydrogenase. The basis of its neurotoxicity is oxidative stress in the wake of cellular energy failure. alpha-Phenyl-tert-butyl-nitrone (PBN), a spin-trapping agent with free radical-scavenging capability, has shown protective effects in various models of experimental brain insults. The effect of PBN on the 3-NP neurotoxicity paradigm was evaluated in this study.


METHODS
Two groups of adult male mice receiving daily systemic 3-NP administration were pretreated with PBN or normal saline respectively for 5 days. After the treatment course, motor dysfunction and the volume of cerebral lesions were quantitatively evaluated. Cellular apoptosis and expressions of glial fibrillary acidic protein (GFAP) and cyclooxygenase-2 (COX-2) in the brain were compared between the 2 groups.


RESULTS
All mice treated with normal saline and 3-NP survived but developed mild motor dysfunction. Apoptosis of striatal cells was noted in the absence of destructive cerebral lesions. In contrast, combined treatment with PBN and 3-NP resulted in more severe motor dysfunction and higher mortality in experimental animals. Destructive lesions with cellular necrosis, and enhanced expressions of GFAP and COX-2 were noted in the striatum.


CONCLUSIONS
3-NP neurotoxicity was paradoxically accentuated by the combined treatment with PBN and 3-NP. Metabolic clearance of 3-NP is probably impaired by PBN and the increased oxidative stress caused by higher 3-NP levels may exceed the free radical-scavenging ability of PBN. The shift from apoptotic to necrotic changes with increased 3-NP toxicity is in accord with the theory that cellular energy reserves determine the pattern of cellular death.
Lan
Min-Yu
MY
Department of Neurology, Chang Gung Memorial Hospital, Kaohsiung, ROC.
Chang
Yung-Yee
YY
Chen
Shun-Sheng
SS
Wu
Hsiu-Shan
HS
Chen
Wei-Hsi
WH
Liu
Jia-Shou
JS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D003497:Cyclic N-Oxides; D051546:Cyclooxygenase 2; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009574:Nitro Compounds; D009589:Nitrogen Oxides / Q000494:pharmacology*; D011422:Propionates / Q000633:toxicity*; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis
D003497:Cyclic N-Oxides; D005904:Glial Fibrillary Acidic Protein; D009574:Nitro Compounds; D009589:Nitrogen Oxides; D011422:Propionates; C029217:phenyl-N-tert-butylnitrone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C015392:3-nitropropionic acid