Cucurbitacin E Modulates Cognitive Impairment Associated with Insulin Resistance-Induced Diabetes via its Anti-Inflammatory Properties and Activation of the PI3K/AKT Signalling Pathway

Abstract

Type 2 diabetes-induced insulin resistance has been linked to neurodegenerative dementia. Natural plant compounds have been established to influence the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B signalling pathway, offering therapeutic benefits in diseased conditions. Therefore, this study investigated the effects of cucurbitacin E (CuE) on the PI3K/AKT signalling pathway in insulin resistance-related cognitive decline in the prefrontal cortex. Forty-eight rats were divided into six groups: control, streptozotocin (STZ) (60 mg/kg), STZ + CuE (0.5 mg/kg), STZ + metformin (MTF) (150 mg/kg), CuE only, and metformin only. Hyperglycaemia was induced using a single intraperitoneal dose of STZ, followed by 28 days of CuE and MTF treatment. MTF was administered orally with the use of a well-calibrated oral gavage, while STZ and CuE were administered intraperitoneally. Behavioural performance, inflammatory cytokines (interleukin-1β, interleukin-9, and tumour necrotic factor-alpha) and PI3K/AKT gene expression were evaluated. CuE significantly (p < 0.05) reduced blood glucose and insulin resistance compared to diabetic rats and improved memory function, as shown by reduced escape latency in the Morris water maze test and discriminatory index in the novel object recognition test. CuE also significantly (p < 0.05) attenuated elevated inflammatory markers and upregulated PI3K/AKT expression. These findings suggest that CuE improves cognitive function in diabetic conditions, likely through its anti-inflammatory action and activation of the PI3K/AKT pathway.