Abstract
Advanced glycation end products (AGEs) are a group of modified proteins and/or lipids with damaging potential. AGEs-RAGE pathway plays a critical role to induce neurodegenerative encephalopathy. Statins can reduce the expression of AGEs-induced AGEs receptor (RAGE) in the aorta. It is not clear whether statins have potential benefits on AGEs-induced cognitive impairment. In this study, the effects of atorvastatin (ATV) on inflammation and oxidation stress in the cerebral cortex were investigated, and the underlying mechanisms were explored. Apolipoprotein E (ApoE)-/- male mice were divided into four groups: control, AGEs, AGEs + ALT711 (Alagebrium chloride) and AGEs + ATV. β-amyloid (Aβ) formation in the cerebral cortex was assessed through Congo red staining and the functional state of neurons was evaluated by Nissl's staining. Immunostaining was performed to assess the accumulation of AGEs in the cerebral cortex. The expressions of mRNA and protein of RAGE, Nuclear factor kappa B (NF-κB) p65 and Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) p47phox were detected by real-time polymerase chain reaction (PCR) and western blot. There were significant increases in AGEs deposit, Aβ formation, and the expressions of RAGE, NF-κB p65, and NADPH oxidase p47phox, and a decrease Nissl body in AGEs group compared with control group. ALT711 group recovered above change compared with AGEs group. Atorvastatin reduced Aβ formation and suppressed AGEs-induced expressions of NF-κB p65 and NADPH oxidase p47phox. Atorvastatin has little effects on AGEs deposit and RAGE expressions. Atorvastatin alleviates AGEs-induced neuronal impairment by alleviating inflammation and oxidative stress via inhibiting NADPH oxidase-NF-κB pathway.
Highlights
There is close association between type 2 diabetes and cognitive impairment
It was reported that advanced glycation end products (AGEs) could participate and accelerate the development and progression of diabetic complications, including neurodegenerative diseases [2]
AGEs-receptors for AGEs (RAGE) system triggers the generation of reactive oxygen species (ROS) by activating nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase)[8], which activates NF-κB and induces subsequent transcription of related genes, including endothelin-1, tissue factor, interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α(TNF-α) [9,10,11]
Summary
40 male ApoE-/- mice were randomly divided into four groups: control, AGEs (30mg/kg/day), AGEs (30mg/kg/day) + ALT711 (1mg/kg/day) and AGEs (30mg/kg/day) + ATV (10mg/kg/day). The animals were fed with a high-fat diet consisting of 42% fat, 19% crude protein and 39% carbohydrate (Slaccas, Shanghai, China) at a controlled temperature of 22 ± 2 °C for 10 weeks. Those mice were randomly divided into four groups: Control (n = 10), AGEs (30 mg/kg/day) (n = 10), AGEs (30 mg/kg/day) + ALT711 (AGEs inhibitors, alagebrium 1 mg/kg/day) (n = 10) and AGEs (30 mg/kg/day) + ATV (atorvastatin 10 mg/kg/day) (n = 10). The reaction mixture was incubated by protecting from light for 24 hours They were filtered through 0.22 μm filter and incubated at 37 °C for 8 weeks. The glycated-BSA was freeze-dried and stored at 4 °C
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