Methylglyoxal and carboxyethyllysine reduce glutamate uptake and S100B secretion in the hippocampus independently of RAGE activation.

Diabetes is a metabolic disease characterized by high fasting-glucose levels. Diabetic complications have been associated with hyperglycemia and high levels of reactive compounds, such as methylglyoxal (MG) and advanced glycation endproducts (AGEs) formation derived from glucose. Diabetic patients have a higher risk of developing neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. Herein, we examined the effect of high glucose, MG and carboxyethyllysine (CEL), a MG-derived AGE of lysine, on oxidative, metabolic and astrocyte-specific parameters in acute hippocampal slices, and investigated some of the mechanisms that could mediate these effects. Glucose, MG and CEL did not alter reactive oxygen species (ROS) formation, glucose uptake or glutamine synthetase activity. However, glutamate uptake and S100B secretion were decreased after MG and CEL exposure. RAGE activation and glycation reactions, examined by aminoguanidine and L-lysine co-incubation, did not mediate these changes. Acute MG and CEL exposure, but not glucose, were able to induce similar effects on hippocampal slices, suggesting that conditions of high glucose concentrations are primarily toxic by elevating the rates of these glycation compounds, such as MG, and by generation of protein cross-links. Alterations in the secretion of S100B and the glutamatergic activity mediated by MG and AGEs can contribute to the brain dysfunction observed in diabetic patients.

Effects of glyoxal or methylglyoxal on the metabolism of amino acids, lactate, glucose and acetate in the cerebral cortex of young and adult rats.

The in vitro effects of glyoxal and methylglyoxal on the metabolism of glycine, alanine, leucine, glutamate, glutamine, glucose, lactate and acetate were evaluated in cortico-cerebral slices from young (10-day-old) or adult (3-month-old) rats. In a first set of experiments with cortico-cerebral slices from young animals, the compounds glyoxal or methylglyoxal at 400 microM, increased the oxidation of alanine, leucine and glycine to CO(2) and decreased the protein synthesis from these amino acids. Lipid synthesis from alanine, leucine and glycine was not changed in the cortico-cerebral slices from young rats after glyoxals exposure. Moreover, glutamine oxidation to CO(2) decreased by glyoxals exposure, but glutamate oxidation was not affected. In a second set of experiments with brain slices from adult animals, glycine metabolism (oxidation to CO(2), conversion to lipids or incorporation into proteins) was not changed by glyoxals exposure. In addition, the oxidation rates of glucose, lactate, acetate, glutamine and glutamate to CO(2) were also not modified. Taken together, these results indicate that glyoxal disrupts the energetic metabolism of the rat cerebral cortex in vitro. However, only young animals were susceptible to such events, suggesting that the immature cerebral cortex is less capable of dealing with glyoxal than the mature one.

Ontogenetic changes in glial fibrillary acid protein phosphorylation, glutamate uptake and glutamine synthetase activity in olfactory bulb of rats.

Phosphorylation of the glial fibrillary acidic protein (GFAP) in hippocampal and cerebellar slices from immature rats is stimulated by glutamate. This effect occurs via a group II metabotropic glutamate receptor in the hippocampus and an NMDA ionotropic receptor in the cerebellum. We investigated the glutamate modulation of GFAP phosphorylation in the olfactory bulb slices of Wistar rats of different ages (post-natal day 15 = P15, post-natal day 21 = P21 and post-natal day 60 = P60). Our results showed that glutamate stimulates GFAP phosphorylation in young animals and this is mediated by NMDA receptors. We also observed a decrease in glutamate uptake at P60 compared to P15, a finding similar to that found in the hippocampus. The activity of glutamine synthetase was elevated after birth, but was found to decrease with development from P21 to P60. Together, these data confirm the importance of glutamatergic transmission in the olfactory bulb, its developmental regulation in this brain structure and extends the concept of glial involvement in glutamatergic neuron-glial communication.