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2-deoxyglucose enhances 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced ATP loss in the mouse brain
P Chan1, J W Langston, I Irwin
1California Parkinson's Foundation, San Jose.
Abstract:
The effects of 2-deoxyglucose (2-DG), an inhibitor of the uptake and use of glucose, on ATP loss caused by the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were determined in the mouse brain. 2-DG alone had no effect on brain ATP levels, but when administered 30 min before MPTP exposure, 2-DG significantly enhanced MPTP-induced ATP reduction. This was reflected as an increase in ATP loss in the striatum (from 15 to 27%) as well as a significant decrease in ATP in the cerebellar cortex, an area of the brain that was not affected after exposure to MPTP alone. In mice pretreated with 2-DG, striatal ATP levels remained significantly decreased for > 8 h after MPTP administration. In contrast, ATP levels in the cerebellar cortex returned to normal values within 4 h from MPTP exposure. Mazindol, a catecholamine uptake blocker, completely protected against MPTP-induced loss of striatal ATP in the absence of 2-DG, but it only partially prevented striatal ATP decrease after administration of both 2-DG and MPTP; mazindol was also ineffective in protecting against ATP loss caused by 2-DG and MPTP in the cerebellar cortex. 2-DG/MPTP-induced ATP loss appeared to be associated with the presence of the 1-methyl-4-phenylpyridinium (MPP+) metabolite because (1) the pattern of ATP recovery in the striatum and cerebellar cortex appeared to reflect the pattern of MPP+ clearance from these areas of the brain (i.e., significant MPP+ levels persisted longer in the striatum than in the cerebellar cortex), and (2) ATP decrease was completely prevented by blocking the conversion of MPTP to MPP+ with the monoamine oxidase B inhibitor deprenyl.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
2-deoxyglucose enhances neurotoxin MPTP
Area of Science:
- Neuroscience
- Biochemistry
- Toxicology
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes ATP loss in the brain.
- Glucose metabolism is critical for maintaining ATP levels in neurons.
Purpose of the Study:
- To investigate the effects of 2-deoxyglucose (2-DG), a glucose metabolism inhibitor, on MPTP-induced ATP loss in the mouse brain.
- To elucidate the mechanisms underlying the interaction between glucose metabolism and MPTP neurotoxicity.
Main Methods:
- Mice were pretreated with 2-DG before MPTP exposure.
- ATP levels in different brain regions (striatum, cerebellar cortex) were measured at various time points post-MPTP administration.
- The role of catecholamine uptake and MPTP metabolism was assessed using mazindol and deprenyl, respectively.
Main Results:
- 2-DG alone did not affect brain ATP levels.
- 2-DG pretreatment significantly enhanced MPTP-induced ATP reduction in the striatum and induced ATP loss in the cerebellar cortex.
- Striatal ATP reduction persisted for over 8 hours in 2-DG/MPTP-treated mice.
- Mazindol partially protected against ATP loss in the striatum but not the cerebellum.
- Deprenyl completely prevented ATP decrease, indicating the involvement of the MPP+ metabolite.
Conclusions:
- 2-DG exacerbates MPTP neurotoxicity by potentiating ATP depletion in a time- and region-dependent manner.
- The findings highlight the critical role of glucose metabolism in neuronal vulnerability to MPTP.
- MPTP-induced ATP loss is linked to its metabolite MPP+ and is influenced by catecholamine uptake mechanisms.