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.
Samantaray
Supriti
S
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Knaryan
Varduhi H
VH
Butler
Jonathan T
JT
Ray
Swapan K
SK
Banik
Naren L
NL
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