Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal cells--protection by carbonyl scavengers.

Advanced glycation end products (AGEs) are found in various intraneuronal protein deposits such as neurofibrillary tangles in Alzheimer's disease and Lewy bodies in Parkinson's disease. Among the many reactive carbonyl compounds and AGE precursors, methylglyoxal is most likely to contribute to intracellular AGE formation, since it is extremely reactive and constantly produced by degradation of triosephosphates. Furthermore, methylglyoxal levels increase under pathophysiological conditions, for example, when trisosephosphate levels are elevated, the expression or activity of glyoxalase I is decreased, as is the case when the concentration of reduced glutathione, the rate-determining co-factor of glyoxalase I, is low. However, the effects of methylglyoxal on mitochondrial function and energy levels have not been studied in detail. In this study, we show that methylglyoxal increases the formation of intracellular reactive oxygen species and lactate in SH-SY5Y neuroblastoma cells. Methylglyoxal also decreases mitochondrial membrane potential and intracellular ATP levels, suggesting that carbonyl stress-induced loss of mitochondrial integrity could contribute to the cytotoxicity of methylglyoxal. The methylglyoxal-induced effects such as ATP depletion and mitochondrial dysfunction can be prevented by pre-incubation of the cells with the carbonyl scavengers aminoguanidine and tenilsetam. In a clinical context, these compounds could not only offer a promising therapeutic strategy to reduce intracellular AGE-accumulation, but also to decrease the dicarbonyl-induced impairment of energy production in aging and neurodegeneration.