Biphasic mechanism of the toxicity induced by 1-methyl-4-phenylpyridinium ion (MPP+) as revealed by dynamic changes in glucose metabolism in rat brain slices.
1-Methyl-4-phenylpyridinium (MPP+) is a well-known neurotoxin which causes a clinical syndrome similar to Parkinson's disease. The classical mechanism of MPP+ toxicity involves its entry into cells through the dopamine transporter (DAT) to inhibit aerobic glucose metabolism, while recent studies suggest that an oxidative mechanism may contribute to the toxicity of MPP+. However, it has not been adequately determined what role these two mechanisms play in the development of neurotoxicity after MPP+ loading in the brain. To clarify this issue, MPP+ was added directly to fresh rat brain slices and the dynamic changes in the cerebral glucose metabolic rate (CMRglc) produced by MPP+ were serially and two-dimensionally measured using the dynamic positron autoradiography technique with [(18)F]2-fluoro-2-deoxy-D-glucose as a tracer. MPP+ dose-dependently increased CMRglc in each of the brain regions examined, reflecting enhanced glycolysis compensating for the decrease in aerobic metabolism. Treatment with DAT inhibitor GBR 12909 significantly attenuated the enhanced glycolysis induced by 10 microM MPP+ in the striatum. Treatment with free radical spin trap alpha-phenyl-N-tert-butylnitrone (PBN) significantly attenuated the enhancement of glycolysis induced by 100 microM MPP+ in all brain regions. These results suggest that the mechanism of the toxicity of MPP+ is biphasic and consists of a DAT-mediated mechanism selective for dopaminergic regions at a lower concentration of MPP+ (10 microM), and an oxidative mechanism that occurs at a higher concentration of MPP+ (100 microM) and is not restricted to dopaminergic regions.
Maruoka
Nobuyuki
N
Department of Neuropsychiatry, University of Fukui, Fukui 910-1193, Japan.
Murata
Tetsuhito
T
Omata
Naoto
N
Takashima
Yasuhiro
Y
Fujibayashi
Yasuhisa
Y
Wada
Yuji
Y
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects*; D015259:Dopamine Agents / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D004579:Electron Transport / Q000187:drug effects; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008959:Models, Neurological; D015233:Models, Statistical; D010084:Oxidation-Reduction; D010879:Piperazines / Q000494:pharmacology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D051381:Rats; D017208:Rats, Wistar
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D010879:Piperazines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C043425:vanoxerine; D005947:Glucose; D015655:1-Methyl-4-phenylpyridinium