Potential of nobiletin against Alzheimer's disease through inhibiting neuroinflammation

Objective: This study aimed to explore the mechanism of Nobiletin attenuating Alzheimer's disease (AD) by inhibiting neuroinflammation.

Methods: The expression of inflammatory cytokines and HMGB-1 in serum of AD patients were examined. Microglia (MGs) were treated with different doses of Nobiletin before LPS and Nigericin induction. Cell viability and Apoptosis were determined by CCK-8 and TUNEL assays, respectively. APP/PS1 mice were gavaged with Nobiletin, and Morris water maze (MWM) was established to record swimming speed, escape latency, the number of platform crossings, and time spent in the platform quadrant. MGs activation in brain tissues was evaluated by immunofluorescence. The expression of pyroptosis-related proteins, inflammatory cytokines, and HMGB-1 was determined in the hippocampus and MGs.

Results: The levels of inflammatory cytokines and HMGB-1 were high in serum of AD patients. Treatment with different concentrations of Nobiletin prominently enhanced cell viability and reduced Apoptosis and the expression of inflammatory cytokine and pyroptosis-related proteins in LPS + Nigericin-induced MGs. Gavage of different doses of Nobiletin into APP/PS1 mice shortened the escape latency in mice, diminished MGs activation in brain tissues, and remarkably elevated the number of platform crossings and the time spent in the platform quadrant without obvious change in swimming speed, suggesting that Nobiletin improved the spatial learning and memory abilities in APP/PS1 mice. The expression of pyroptosis-related proteins, HMGB-1, and inflammatory cytokines was decreased dramatically by Nobiletin in the hippocampus of APP/PS1 mice.

Conclusions: Nobiletin can inhibit neuroinflammation by inhibiting HMGB-1, pyroptosis-related proteins, and inflammatory cytokines, thus mitigating AD.