Depletion of MGO or Its Derivatives Ameliorate CUMS-Induced Neuroinflammation.

Abstract

Advanced glycation end products (AGEs) are a series of structurally complex and harmful compounds formed through the reaction between the carbonyl group of reducing sugars (such as glucose and fructose) and the free amino groups of proteins, lipids, or nucleic acids. Excessive accumulation of AGEs in the body can trigger oxidative stress, induce inflammatory responses, and contribute to the development of diabetes, atherosclerosis, and neurological disorders. Within the category of dicarbonyl compounds, methylglyoxal (MGO)-a byproduct resulting from glucose degradation-serves as a pivotal precursor in the formation of AGEs and the induction of neurotoxicity. Specifically, AGEs generated from MGO display significant cytotoxicity toward cells in the central nervous system. Therefore, we aimed to investigate the role of MGO-AGEs in neuroinflammation mediated by CUMS. Interestingly, we found that the overexpression of glyoxalase 1 (GLO1) reduced the levels of MGO in corticosterone-treated microglia, thereby alleviating the inflammatory response. Furthermore, overexpression of GLO1 in the hippocampus of chronically stressed mice reduced MGO levels, mitigating CUMS-induced neuroinflammation and cognitive impairment. Additionally, when using the receptor for advanced glycation end products (RAGE) inhibitor FPS-ZM1 in primary microglia cells, we observed that despite corticosterone-induced elevation of MGO, no significant inflammatory response occurred. This suggests that RAGE clearance can reduce MGO-AGE-mediated neurotoxicity. Subsequently, we used FPS-ZM1 to treat chronically stressed mice and found that it significantly ameliorated neuroinflammation and cognitive dysfunction. These results suggest that targeting MGO metabolism could serve as a therapeutic approach to manage neuroinflammation in stress-related mental disorders.