期刊
JOURNAL OF NEUROCHEMISTRY
卷 104, 期 5, 页码 1309-1320出版社
BLACKWELL PUBLISHING
DOI: 10.1111/j.1471-4159.2007.05091.x
关键词
dopamine transporter; experimental parkinsonism; monoamine oxidase-B; MPP+; Parkinson's disease; spinal cord
资金
- NCI NIH HHS [CA-91460] Funding Source: Medline
- NINDS NIH HHS [NS-45967, NS-57811, NS-41088] Funding Source: Medline
- PHS HHS [C06 RRO-15455] Funding Source: Medline
We examined neurodegeneration in spinal cord (SC) and role of such extra-nigral degeneration in MPTP-induced experimental parkinsonism in C57BL/6N mice. HPLC-photodiode array analysis confirmed presence of the active neurotoxin MPP+ in SC after single injection of MPTP ( 25 mg/kg, i. p.). Mitochondrial enzyme monoamine oxidase-B (MAO-B) responsible for in vivo conversion of MPTP to MPP+ was inhibited in SC by pre-treatment with L-deprenyl, a specific inhibitor of MAO-B. Besides in vitro conversion of MPTP to MPP+ occurred by SC mitochondrial preparation, which was inhibited by L-deprenyl implicating SC as a specific target of MPTP-neurotoxicity. Double immunofluorescent labeling and spectrofluorimetric assay via kynuramine oxidation showed MAO-B expression and activity in SC neurons. Localization of dopamine transporter immunoreactivity in SC along with specific uptake of H-3-MPP+ by SC synaptosomal preparation further confirmed SC as target of MPTP-neurotoxicity. Compared with control, increased neuronal death on the seventh day in SC of mice injected with MPTP ( 2 x 25 mg/kg, at 6 h interval) strongly suggested SC degeneration in pre-symptomatic phase of MPTP-induced experimental parkinsonism. Such extra-nigral neurodegeneration in Parkinson's disease indicated novel molecular mechanism preceding nigrostriatal degeneration and suggested designing broad therapeutic intervention for this complex movement disorder.
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