H MRS identifies lactate rise in the striatum of MPTP-treated C57BL/6 mice.
Mitochondrial dysfunction has been implicated in the death of nigrostriatal dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated experimental models of Parkinson's disease (PD). Here we utilized proton magnetic resonance spectroscopy ((1)H MRS) to identify changes in energy metabolism in the striatum of MPTP-treated C57BL/6 mice. Remarkable increases in lactate/creatine (Lac/Cr) ratio were observed at 2 h and then quickly returned to about the basal level by 7 h after injection of MPTP. Neurochemical and Western blot analyses revealed that dopamine contents and protein levels of tyrosine hydroxylase and dopamine transporter in the striatum were profoundly decreased at 3 days after MPTP treatment. Pretreatment with deprenyl, a monoamine oxidase B inhibitor, or GBR-12909, a dopamine uptake inhibitor, almost completely attenuated both the increases in striatal Lac/Cr ratio and the subsequent loss of dopaminergic nerve terminals in MPTP-treated mice. The present study indicates that (1)H MRS is a sensitive measure of biochemical alterations of the brain in a mouse model of PD, and further shows that the increases in striatal Lac/Cr ratio induced by MPTP may be associated with mitochondrial energy crisis, followed by dopaminergic neurotoxicity.
Koga
Keiko
K
Laboratory of Bioenergetics Research, Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd, Tokushima 771-0192, Japan.
Mori
Atsushi
A
Ohashi
Satoshi
S
Kurihara
Naoki
N
Kitagawa
Hisashi
H
Ishikawa
Makoto
M
Mitsumoto
Yasuhide
Y
Nakai
Masami
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D019344:Lactic Acid / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011522:Protons; D012642:Selegiline / Q000494:pharmacology; D013997:Time Factors
D018765:Dopamine Uptake Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010879:Piperazines; D011522:Protons; D012642:Selegiline; D019344:Lactic Acid; C043425:vanoxerine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine