期刊
JOURNAL OF MOLECULAR NEUROSCIENCE
卷 28, 期 2, 页码 125-141出版社
HUMANA PRESS INC
DOI: 10.1385/JMN:28:2:125
关键词
iron; coenzyme Q(10); apoptosis; ferritin; melanin; Parkinson's disease
资金
- NIA NIH HHS [1R01 AG17059-06] Funding Source: Medline
- NINDS NIH HHS [2R01 NS34566-09] Funding Source: Medline
The exact molecular mechanism of progressive loss of neuromelanin containing nigrostriatal dopaminergic neurons in Parkinson's disease (PD) remains unknown, yet evidence suggests that iron might play an important role in PD pathology. In this study we have determined the neuroprotective role of coenzyme Q(10) (CoQ(10)) in iron-induced apoptosis in cultured human dopaminergic (SK-N-SH) neurons, in metallothionein gene-manipulated mice, and in alpha-synuclein knockout (alpha-synko) mice with a primary objective to assess a possible therapeutic and anti-inflammatory potential for CoQ(10) in PD. Iron-induced mitochondrial damage and apoptosis were characterized by reactive oxygen species production, increased metallothionein and glutathione synthesis, caspase-3 activation, NF-kappa B induction, and decreased Bcl-2 expression, without any significant change in Bax expression. Lower concentrations of FeSO4 (1-10 mu M) induced perinuclear aggregation of mitochondria, whereas higher concentrations (100-250 mu M) induced CoQ(10) depletion, plasma membrane perforations, mitochondrial damage, and nuclear DNA condensation and fragmentation. FeSO4-induced deleterious changes were attenuated by pretreatment with CoQ(10) and by deferoxamine, a potent iron chelator, in SK-N-SH cells. 1-Methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine(MPTP)-induced striatal release of free iron, and NF-kappa B expression were significantly increased; whereas ferritin and melanin synthesis were significantly reduced in the substantia nigra pars compacta (SNpc) of MTdko mice as compared with control(wt) mice, MTtrans mice, and alpha-synko mice. CoQ(10) treatment inhibited MPTP-induced NF-kappa B induction in all of the genotypes. These data suggest that glutathione and metallothionein synthesis might be induced as an attempt to combat iron-induced oxidative stress, whereas exogenous administration of CoQ(10) or of metallothionein induction might provide CoQ(10)-mediated neuroprotection in PD.
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