Diosmetin Targeted at Peroxisome Proliferator-Activated Receptor Gamma Alleviates Advanced Glycation End Products Induced Neuronal Injury.

Abstract

The present study aimed to evaluate the role of diosmetin in alleviating advanced glycation end products (AGEs)-induced Alzheimer’s disease (AD)-like pathology and to clarify the action mechanisms. Before stimulation with AGEs (200 μg/mL), SH-SY5Y cells were treated with diosmetin (10 μmol/L), increasing cell viability. The induction of AGEs on the reactive oxygen species overproduction and downregulation of antioxidant enzyme activities, including superoxide dismutase, glutathione peroxidase, and catalase, were ameliorated by diosmetin. Amyloid precursor protein upregulation, accompanied by increased production of amyloid-β, caused by AGEs, was reversed by diosmetin. In the presence of diosmetin, not only β-site amyloid precursor protein cleaving enzyme1 expression was lowered, but the protein levels of insulin-degrading enzyme and neprilysin were elevated. Diosmetin protects SH-SY5Y cells from endoplasmic reticulum (ER) stress response to AGEs by suppressing ER stress-induced glucose regulated protein 78, thereby downregulating protein kinase R-like endoplasmic reticulum kinase, eukaryotic initiation factor 2 α, activating transcription factor 4, and C/EBP homologous protein. Diosmetin-pretreated cells had a lower degree of apoptotic DNA fragmentation; this effect may be associated with B-cell lymphoma (Bcl) 2 protein upregulation, Bcl-2-associated X protein downregulation, and decreased activities of caspase-12/-9/-3. The reversion of diosmetin on the AGEs-induced harmful effects was similar to that produced by pioglitazone. The peroxisome proliferator-activated receptor (PPAR)γ antagonist T0070907 (5 μmol/L) abolished the beneficial effects of diosmetin on AGEs-treated SH-SY5Y cells, indicating the involvement of PPARγ. We conclude that diosmetin protects neuroblastoma cells against AGEs-induced ER injury via multiple mechanisms and may be a potential option for AD.