Neuroprotective effects of nuciferine on high-fat diet-induced cognitive dysfunction in obese mice: Role of insulin resistance, neuroinflammation, and oxidative stress

High-fat diets (HFDs) trigger oxidative stress, insulin resistance (IR), and inflammatory responses in the body, leading to cognitive dysfunction. This study aimed to elucidate the effects of nuciferine on HFD-induced IR and cognitive impairment in the central nervous system of obese mice and further identify the possible underlying mechanisms. In behavioral experiments, nuciferine administration increased the total distance moved, the number of times mice entered the open arm, the duration of open dwell time, and the number of alternations while shortening the latency to escape. Nuciferine suppressed HFD-induced synaptic structure damage, as evidenced by the increased expressions of neurotrophic factor BDNF and synaptic function proteins SYN, SNAP-25, and PSD-95. In addition, nuciferine effectively ameliorated HFD-induced IR by IRS/PI3K/AKT pathway, alleviated HFD-induced neurological damage through AMPK/SIRT1 pathway, and improved cognitive impairment via the Aβ-tau-neuroinflammation axis. Therefore, nuciferine could be a new food-derived neuroprotective agent to counteract HFD-induced damage.