Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis.

Type 2 diabetes-associated cognitive dysfunction (TDACD) is a recognized metabolic brain disorder with limited therapeutic options. This preclinical study investigated whether isoorientin (ISO) confers neuroprotection in TDACD and examined the involvement of the glycogen synthase kinase-3β/nuclear factor erythroid 2-related factor 2 (GSK3β/Nrf2) pathway in its effects. A mouse model of TDACD was induced by high-fat diet and streptozotocin. Mice were administered ISO for six weeks. The systemic metabolism and cognitive behavior were evaluated. The synaptic protein expression, apoptosis, tau phosphorylation, oxidative stress in the brain were detected to identify the pathological signature. The activity of GSK3β and the expression of its downstream targets Nrf2 and heme oxygenase-1 (HO-1) were analyzed to elucidate the mechanism. ISO improved systemic glucose metabolism and alleviated hepatic steatosis, and reversed cognitive deficits. In the brain, ISO restored synaptic proteins (PSD-95, BDNF, soluble α-synuclein), exerted anti-apoptotic effects (increased Bcl-2/Bax ratio, decreased cleaved caspase-3), and attenuated oxidative stress and mitochondrial damage. Mechanistically, ISO inhibited GSK3β activity, promoted Nrf2 nuclear accumulation, upregulated HO-1 expression, and reduced tau phosphorylation at Ser396. These findings demonstrate that ISO exerts a neuroprotective effect in TDACD model by inhibiting oxidative stress via GSK3β/Nrf2 pathway, and highlight ISO as a potential therapeutic candidate for TDACD.