3‐Nitropropionic Acid Neurotoxicity Is Attenuated in Copper/Zinc Superoxide Dismutase Transgenic Mice

Abstract: The mitochondrial toxin 3‐nitropropionic acid (3‐NP) produces selective striatal lesions in both experimental animals and humans. The pathogenesis of the lesions involves secondary excitotoxicity that may then lead to free radical generation. To test this further we examined the effects of 3‐NP in both transgenic (Tg) mice that carry the complete sequence for the human copper/zinc superoxide dismutase (SOD) gene as well as non‐Tg littermate controls. The Tg‐SOD mice showed a pronounced attenuation of Nissl‐stained striatal lesions compared with non‐Tg mice. Systemic administration of 3‐NP resulted in production of hydroxyl free radicals as assessed by the conversion of salicylate to 2,3‐ and 2,5‐dihydroxybenzoic acid. This production was attenuated significantly in Tg‐SOD mice. In a similar way, 3‐NP produced significant increases in 3‐nitrotyrosine/tyrosine, a marker for peroxynitrite‐mediated damage, which were significantly attenuated in Tg‐SOD mice. These results support that oxygen free radicals and peroxynitrite play an important role in the pathogenesis of 3‐NP neurotoxicity.

[1]  B. Rosen,et al.  Age‐Dependent Vulnerability of the Striatum to the Mitochondrial Toxin 3‐Nitropropionic Acid , 1993, Journal of neurochemistry.

[2]  A. Ludolph,et al.  3-Nitropropionic Acid - Exogenous Animal Neurotoxin and Possible Human Striatal Toxin , 1991, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[3]  B. Freeman,et al.  Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Penney,et al.  3‐Nitropropionic Acid Toxicity in the Striatum , 1994, Journal of neurochemistry.

[5]  C. Epstein,et al.  Cold‐induced brain edema and infarction are reduced in transgenic mice overexpressing CuZn‐Superoxide dismutase , 1991, Annals of neurology.

[6]  M. Lovett,et al.  Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Coyle,et al.  Oxidative stress, glutamate, and neurodegenerative disorders. , 1993, Science.

[8]  C. Epstein,et al.  Rapid Communication: Attenuation of Methamphetamine‐Induced Neurotoxicity in Copper/Zinc Superoxide Dismutase Transgenic Mice , 1994, Journal of neurochemistry.

[9]  C. Epstein,et al.  CuZn-superoxide dismutase (CuZnSOD) transgenic mice show resistance to the lethal effects of methylenedioxyamphetamine (MDA) and of methylenedioxymethamphetamine (MDMA) , 1994, Brain Research.

[10]  R. Floyd,et al.  Sensitive assay of hydroxyl free radical formation utilizing high pressure liquid chromatography with electrochemical detection of phenol and salicylate hydroxylation products. , 1984, Journal of biochemical and biophysical methods.

[11]  C. Epstein,et al.  Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[12]  J. Bockaert,et al.  NMDA-dependent superoxide production and neurotoxicity , 1993, Nature.

[13]  B. Hyman,et al.  Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  C. Epstein,et al.  Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[15]  W. Koppenol,et al.  On the pH-dependent yield of hydroxyl radical products from peroxynitrite. , 1994, Free radical biology & medicine.

[16]  M. Beal,et al.  Kynurenine Pathway Measurements in Huntington's Disease Striatum: Evidence for Reduced Formation of Kynurenic Acid , 1990, Journal of neurochemistry.

[17]  D. Carpenter,et al.  Inhibition of energy metabolism by 3-nitropropionic acid activates ATP-sensitive potassium channels , 1992, Brain Research.

[18]  J S Beckman,et al.  Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. , 1992, Archives of biochemistry and biophysics.

[19]  J. Dykens.  Isolated Cerebral and Cerebellar Mitochondria Produce Free Radicals when Exposed to Elevated Ca2+ and Na+: Implications for Neurodegeneration , 1994, Journal of neurochemistry.