Dimethyl-2-oxoglutarate but not antioxidants prevents glucose hypometabolism induced neural cell death: implications in the pathogenesis and therapy of Alzheimer's disease.

Cerebral glucose hypometabolism is a cardinal molecular signature of Alzheimer's disease, and its role in the pathogenesis of this disorder is under intensive study in both animal and cell-based models. In the current study, we exposed SH-SY5Y cells (human neuroblastoma cell line) over a period of 48 h to DRB18, an inhibitor of multiple glucose transporters, in different concentrations to develop a state of glucose hypometabolism. Under this metabolic insult, in SH-SY5Y cells a profound dose-dependent neural cell death, an increased production of reactive oxygen radicals, mitochondrial membrane depolarization and a depletion of cellular ATP content were noted; these effects were not prevented by lipid-soluble novel antioxidants such as ferrostatin-1 and liproxstatin-1 or by a general water-soluble antioxidant like N-acetylcysteine. However, dimethyl-2-oxoglutarate, the cell-permeable analogue of 2-oxoglutarate (α-ketoglutarate) which can serve as an alternative fuel during glucose hypometabolism partially prevented both mitochondrial impairments and neural cell death. Thus, dimethyl-2-oxoglutarate may be explored further as a potential neuroprotective compound for Alzheimer's disease, and its effect on amyloid beta metabolism and homeostasis should be examined under glucose hypometabolic stress.