Spinal cord degeneration in C57BL/6N mice following induction of experimental parkinsonism with MPTP.
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 (3)H-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.
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Supriti
S
Samantaray
Varduhi H
VH
Knaryan
Jonathan T
JT
Butler
Swapan K
SK
Ray
Naren L
NL
Banik
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D008159:Lumbar Vertebrae; D020267:MPTP Poisoning / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*; D010302:Parkinson Disease, Secondary / Q000150:complications / Q000378:metabolism*; D013118:Spinal Cord Diseases / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine