Targeting the Keap1/Nrf2 pathway: Ginkgolide B mitigates oxidative stress and neuroinflammation in diabetic cognitive dysfunction.

Diabetic cognitive dysfunction (DCD) is a severe complication of type 2 diabetes mellitus (T2DM). Ginkgolide B (GB), a primary bioactive terpene lactone of Ginkgo biloba, has proven neuroprotective effects in ischemic stroke, yet its role and underlying mechanisms in DCD remain poorly understood. This study aimed to investigate the protective effects of GB against DCD and to elucidate the underlying mechanisms focusing on the Keap1/Nrf2 pathway. For in vivo experiments, db/db mice and high-fat diet/streptozotocin-induced T2DM mice with AAV-mediated Nrf2 knockdown (sh-Nrf2) or overexpression (OE-Nrf2) were treated with GB. For in vitro studies, HT22 neurons and BV2 microglial cells exposed to high glucose were used to assess the effects of GB. The results showed that GB treatment significantly ameliorated hyperglycemia and lipid metabolic disorders in diabetic mice. Behaviorally, GB reversed deficits in cognitive abilities. At the mechanistic level, GB attenuated hippocampal neuronal loss and restored synaptic plasticity, concomitant with the suppression of oxidative stress and neuroinflammation. These neuroprotective effects were mediated by the inhibition of Keap1, leading to Nrf2 activation and the subsequent downregulation of the NLRP3 inflammasome and NF-κB pathways. Notably, the cognitive benefits and neuroprotective effects of GB were completely abolished in sh-Nrf2 mice, whereas Nrf2 overexpression mimicked GB's effects without further additive benefits. Crucially, Surface-plasmon resonance and molecular docking analyses confirmed a strong direct binding affinity between GB and Keap1. These results indicated that GB alleviates DCD by targeting Keap1 to activate the Nrf2 signaling pathway, subsequently inhibiting oxidative stress and neuroinflammation.