2‐Deoxyglucose Enhances 1‐Methyl‐4‐Phenyl‐1, 2, 3, 6‐Tetrahydropyridine‐Induced ATP Loss in the Mouse Brain

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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. Data indicate that impairment of glucose metabolism dramatically enhances the effects of MPTP/MPP+ on cerebral energy supplies, making these effects relatively nonselective for dopaminergic neurons of the nigrostriatal pathway.

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