The impact of exenatide (a GLP-1 agonist) on markers of inflammation and oxidative stress in normal human astrocytes subjected to various glycemic conditions

摘要

GLP-1 agonists such as exenatide and liraglutide are novel drugs for the treatment of diabetes and obesity. While improvements in glycemic control can rely on an incretin effect, the mechanisms behind the loss of weight following therapy have yet to be completely elucidated, and seem to be associated with alterations in eating habits, resulting from changes in cytokines e.g. interleukin 1β (IL-1β) and oxidative signaling in the central nervous system (CNS). Increased levels of IL-1β and reactive oxygen species have been demonstrated to exert anorexigenic properties, and astrocytes appear to actively participate in maintaining the integrity of the CNS, which includes the paracrine secretion of inflammatory cytokines and involvement in the redox status. Therefore, the present study decided to explore the influence of exenatide [a glucagon-like peptide 1 (GLP-1 agonist)] on inflammatory and oxidative stress markers in cultured human astrocytes as a potential target for weight reduction therapies. In an experimental setting, normal human astrocytes were subjected to various glycemic conditions, including 40 mg/dl-hypoglycemic, 100 mg/dl-normoglycemic and 400 mg/dl-hyperglycemic, and exenatide, which is a GLP-1 agonist. The involvement of intracellular signaling by a protein kinase A (PKA) in the action of exenatide was estimated using a specific PKA inhibitor-PKI (–). The expression levels of IL-1β, nuclear factor kappa κB (NFκB), glial-fibrillary acidic protein (GFAP), p22 NADPH oxidase, glutathione peroxidase, catalase, superoxide dismutase 1, and reactive oxidative species were measured. The present study demonstrated that varying glucose concentrations in the culture media did not affect the protein expression or the level of reactive oxygen species. Conversely, exenatide led to an increase in IL-1β in normoglycemic culture conditions, which was accompanied by the increased expression of p22, glutathione peroxidase and the reduced expression of GFAP. Changes in the expression of IL-1β and p22 were dependent on the activation of PKA. The present study concluded that exenatide predominantly affected astrocytes in normoglycemic conditions, and hypothesize that this impact demonstrated one of novel mechanisms associated with astrocyte signaling that may contribute to weight loss.