MPP(+) causes inhibition of cellular energy supply in cerebellar granule cells

A significant loss in ATP levels was found in cerebellar granule cells with 1-methyl-4-phenylpyridinium. Exposure of cerebellar granule cells to low concentrations of 1-methyl-4-phenylpyridinium (100 microM) resulted in a time and dose-dependent decreases in ATP levels and cell death. This neurotoxin caused inhibition of the enzymatic activity of NADH-dehydrogenase of mitochondrial complex I and consequent impairment of mitochondrial electronic transport with a reduction in the depletion of cytosolic NAD(+) levels. Activation of lactate dehydrogenase activity (detected by the increase of the lactate in the culture medium) partially reduced this depletion. Addition of glucose but not pyruvate to the culture medium protected 1-methyl-4-phenylpyridinium-induced cell death. These results suggest the 1-methyl-4-phenylpyridinium causes impairment of cellular energy metabolism with a major dependence on glycolysis as a source of energy. This fact could also explain the partial neuroprotection observed by glucose.