Paradoxical increase in 3-nitropropionic acid neurotoxicity by α-phenyl-tert-butyl-nitrone, a spin-trapping agent

Min Yu Lan, Yung Yee Chang, Shun Sheng Chen, Hsiu Shan Wu, Wei Hsi Chen, Jia Shou Liu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

3 Scopus citations


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, α-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.

Original languageEnglish
Pages (from-to)77-84
Number of pages8
JournalChang Gung Medical Journal
Issue number2
StatePublished - 02 2005
Externally publishedYes


  • 3-nitroptopionic acid
  • Apoptosis
  • Mitochondrion
  • Necrosis
  • Spin-trapping agent


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