Glutamatergic Alterations in STZ-Induced Diabetic Rats Are Reversed by Exendin-4

Diabetes mellitus is a metabolic disorder that results in glucotoxicity and the formation of advanced glycated end products (AGEs), which mediate several systemic adverse effects, particularly in the brain tissue. Alterations in glutamatergic neurotransmission and cognitive impairment have been reported in DM. Exendin-4 (EX-4), an analogue of glucagon-like peptide-1 (GLP-1), appears to have beneficial effects on cognition in rats with chronic hyperglycemia. Herein, we investigated the ability of EX-4 to reverse changes in AGE content and glutamatergic transmission in an animal model of DM looking principally at glutamate uptake and GluN1 subunit content of the N-methyl-D-aspartate (NMDA) receptor. Additionally, we evaluated the effects of EX-4 on in vitro models and the signaling pathway involved in these effects. We found a decrease in glutamate uptake and GluN1 content in the hippocampus of diabetic rats; EX-4 was able to revert these parameters, but had no effect on the other parameters evaluated (glycemia, C-peptide, AGE levels, RAGE, and glyoxalase 1). EX-4 abrogated the decrease in glutamate uptake and GluN1 content caused by methylglyoxal (MG) in hippocampal slices, in addition to leading to an increase in glutamate uptake in astrocyte culture cells and hippocampal slices under basal conditions. The effect of EX-4 on glutamate uptake was mediated by the phosphatidylinositide 3-kinases (PI3K) signaling pathway, which could explain the protective effect of EX-4 in the brain tissue, since PI3K is involved in cell metabolism, inhibition of apoptosis, and reduces inflammatory responses. These results suggest that EX-4 could be used as an adjuvant treatment for brain impairment associated with excitotoxicity.