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Paradoxical increase in 3-nitropropionic acid neurotoxicity by alpha-phenyl-tert-butyl-nitrone, a spin-trapping agent.
Chang Gung Med J. 2005 Feb; 28(2):77-84.CG

Abstract

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.

Authors+Show Affiliations

Department of Neurology, Chang Gung Memorial Hospital, Kaohsiung, ROC.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15880982

Citation

Lan, Min-Yu, et al. "Paradoxical Increase in 3-nitropropionic Acid Neurotoxicity By Alpha-phenyl-tert-butyl-nitrone, a Spin-trapping Agent." Chang Gung Medical Journal, vol. 28, no. 2, 2005, pp. 77-84.
Lan MY, Chang YY, Chen SS, et al. Paradoxical increase in 3-nitropropionic acid neurotoxicity by alpha-phenyl-tert-butyl-nitrone, a spin-trapping agent. Chang Gung Med J. 2005;28(2):77-84.
Lan, M. Y., Chang, Y. Y., Chen, S. S., Wu, H. S., Chen, W. H., & Liu, J. S. (2005). Paradoxical increase in 3-nitropropionic acid neurotoxicity by alpha-phenyl-tert-butyl-nitrone, a spin-trapping agent. Chang Gung Medical Journal, 28(2), 77-84.
Lan MY, et al. Paradoxical Increase in 3-nitropropionic Acid Neurotoxicity By Alpha-phenyl-tert-butyl-nitrone, a Spin-trapping Agent. Chang Gung Med J. 2005;28(2):77-84. PubMed PMID: 15880982.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Paradoxical increase in 3-nitropropionic acid neurotoxicity by alpha-phenyl-tert-butyl-nitrone, a spin-trapping agent. AU - Lan,Min-Yu, AU - Chang,Yung-Yee, AU - Chen,Shun-Sheng, AU - Wu,Hsiu-Shan, AU - Chen,Wei-Hsi, AU - Liu,Jia-Shou, PY - 2005/5/11/pubmed PY - 2005/6/3/medline PY - 2005/5/11/entrez SP - 77 EP - 84 JF - Chang Gung medical journal JO - Chang Gung Med J VL - 28 IS - 2 N2 - 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. SN - 2072-0939 UR - https://www.unboundmedicine.com/medline/citation/15880982/Paradoxical_increase_in_3_nitropropionic_acid_neurotoxicity_by_alpha_phenyl_tert_butyl_nitrone_a_spin_trapping_agent_ L2 - http://cgmj.cgu.edu.tw/2802/280202.pdf DB - PRIME DP - Unbound Medicine ER -