Swietenolide inhibits the TXNIP/NLRP3 pathways via Nrf2 activation to ameliorate cognitive dysfunction in diabetic mice.

Oxidative stress and inflammation play important roles in diabetic-associated cognitive dysfunction (DACD). Swietenolide (Std), isolated from the fruit of Swietenia macrophylla King, exhibits various potent pharmacological activities, including antioxidant, anti-inflammatory, and anti-tumor properties. However, the effects of Std on DACD remains unexplored. We utilized diabetic db/db mice and the hippocampal cell line HT22 to evaluate the effects and underlying molecular mechanisms of Std on DACD. Molecular docking study, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay analyses were conducted to elucidate the molecular mechanisms involved. We found that Std significantly improved cognitive dysfunction in diabetic mice and increased cell viability in HT22 cells under high glucose condition. The reduction in superoxide dismutase (SOD) enzamy activity and glutathione (GSH) level, along with an increase in malondialdehyde (MDA) induced by high glucose in hippocampus, were reversed by Std treatment. Furthermore, Std effectively diminished the levels of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Importantly, Std markedly activated the Nrf2 pathway to inhibit the thioredoxin-interacting protein/NOD-like receptor protein 3 (TXNIP/NLRP3) pathways. However, the neuroprotective effect of Std was significantly weakened by Nrf2 inhibitor ML385. These results indicate that Std provides substantial protection against high glucose-induced hippocampal injury by inhibiting the TXNIP/NLRP3 pathways dependent on Nrf2, which may serve as a promising agent for attenuating DACD.