Empagliflozin alleviates diabetes-induced cognitive impairments by lowering nicotinamide adenine dinucleotide phosphate oxidase-4 expression and potentiating the antioxidant defense system in brain tissue of diabetic rats

Abstract

Background: Diabetes-induced cognitive impairment is a major challenge in patients with uncontrolled diabetes mellitus. It has a complicated pathophysiology, but the role of oxidative stress is central. Therefore, the use of antidiabetic drugs with extra-glycemic effects that reduce oxidative damage may be a promising treatment option.

Methods: Male Wistar rats were randomly divided into four groups as normal, normal treated, diabetic and diabetic treated (n = 8 per group). Type 1 diabetes was induced by a single intraperitoneal dose of streptozotocin (STZ) (40 mg/kg). Two treatment groups received empagliflozin for 5 weeks (20 mg/kg/po). Cognitive ability was evaluated using open field, Elevated Plus Maze (EPM) and the Morris Water Maze (MWM) tests at study completion. Blood and brain tissue samples were collected - and analysis for malondialdehyde (MDA) and glutathione (GLT) content and catalase (CAT) and superoxide dismutase (SOD) enzyme activity were performed. Additionally, expression of nicotinamide adenine dinucleotide phosphate oxidase-4 (Nox-4) enzyme in brain tissue was analyzed using RT-PCR.

Results: STZ increased blood glucose and induced diabetes with oxidative stress by lowering the antioxidant system potency and increasing Nox-4 expression after 5-weeks in brain tissue accompanied by reduction in cognitive performance. Also, diabetes induced anxiety-like behavior and impaired spatial memory in MWM, EPM and open field tests. However, empagliflozin reversed these changes, improving SOD and CAT activity, GLT content and reducing Nox-4 expression and MDA concentration in brain tissue while improving cognitive ability. It reduced anxiety and depression-related activities. It also improved spatial memory in MWM test.

Conclusion: Uncontrolled diabetes negatively impacts mental function and impairs learning and cognitive performance via oxidative stress induction, the Nox-4 enzyme playing a central role. Empagliflozin reverses these effects, improving cognitive ability via promoting the anti-oxidative system and damping Nox-4 free radical generator enzyme expression. Therefore, empagliflozin is a promising treatment, providing both antidiabetic and extra-glycemic benefits for improving brain function in the diabetic milieu.

Keywords: Cognition; Diabetes mellitus; Empagliflozin; Nox-4; Oxidative stress; Sodium-glucose cotransporter 2 inhibitor.