A novel compound AB-38b improves diabetes-associated cognitive decline in mice via activation of Nrf2/ARE pathway

Abstract

Objective: Diabetes-associated cognitive decline (DACD) is increasingly being concerned, and oxidative stress plays a vital role in the pathological process. AB-38b is a novel synthetic compound with two specific active groups of biphenyl dicarboxylate and α, β unsaturated ketone, showing good antioxidant activity. The aim of this study was to investigate the ameliorative effects of AB-38b on DACD in mice, and to explore the possible mechanisms from glyoxylase 1 (Glo-1) enhancement and NF-E2-related factor-2 (Nrf2) activation.

Methods: Experimental type 2 mouse model of diabetes with C57BL/6 mice was made through high-fat diet combining with intraperitoneal streptozotocin. Diabetic mice were treated by gavage with AB-38b (0, 10, 20 and 40 mg/kg) or resveratrol (40 mg/kg), a typical inducer of Nrf2, for 8 weeks. Cognitive performances were evaluated by the novel object recognition task. Then brain tissues were collected to assess hippocampal damages, protein glycation, Glo-1 functions and protein expression, and the classic Nrf2/ARE pathway.

Result: AB-38b markedly increased the preference index to novel object and the number of neurons in hippocampal CA1 area of diabetic mice. AB-38b significantly elevated the activity and protein of Glo-1, while reduced the levels of advanced glycation end products (AGEs) and protein expression of its receptor RAGE. Moreover, AB-38b raised Nrf2 expression and phosphorylation, as well as the protein expression and enzymatic activity of γ-glutamylcysteine synthetase, a well-known gene of Nrf2/ARE pathway, in hippocampus of the diabetic mice.

Conclusion: AB-38b improved the cognitive performances of diabetic mice, which was achieved via up-regulation of Glo-1 and activation of Nrf2/ARE pathway.

Keywords: AB-38b; AGEs-RAGE system; Diabetic encephalopathy; Glyoxylase 1; Nrf2/ARE pathway.