期刊
EXPERIMENTAL NEUROLOGY
卷 167, 期 1, 页码 189-195出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1006/exnr.2000.7525
关键词
MPTP; malonate; free radicals; 3-nitropropionic acid; Parkinson's disease; Huntington's disease
资金
- NIA NIH HHS [AG13846] Funding Source: Medline
- NINDS NIH HHS [NS37102, NS38180, NS35255] Funding Source: Medline
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS035255] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P30AG013846] Funding Source: NIH RePORTER
There is substantial evidence implicating mitochondrial dysfunction and free radical generation as major mechanisms of neuronal death in neurodegenerative diseases. The major free radical scavenging enzyme in mitochondria is manganese superoxide dismutase (SOD2). In the present study we investigated the susceptibility of mice with a partial deficiency of SOD2 to the neurotoxins 1-methyl-4-phenyl-1,2,5,6-tetrahydro-pyridine (MPTP), 3-nitropropionic acid (3-NP), and malonate, which are commonly used animal models of Parkinson's and Huntington's disease, Heterozygous SOD2 knockout (SOD2(+/-)) mice showed no evidence of neuropathological or behavioral abnormalities at 2-4 months of age. Compared to littermate wild-type mice, mice with partial SOD2 deficiency showed increased vulnerability to dopamine depletion after systemic MPTP treatment and significantly larger striatal lesions produced by both 3-NP and malonate. SOD2(+/-) mice also showed an increased production of hydroxyl radicals after malonate injection measured with the salicylate hydroxyl radical trapping method. These results provide further evidence that reactive oxygen species play an important role in the neurotoxicity of MPTP, malonate, and 3-NP. These findings show that a subclinical deficiency in a free radical scavenging enzyme may act in concert with environmental toxins to produce selective neurodegeneration. (C) 2001 Academic Press.
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