Nanoformulated fisetin ameliorates Alzheimer's disease via reducing proinflammatory cytokines and activating the NRF2/HO-1 pathway

Aim: The study aimed to evaluate the neuroprotective effect of a chitosan-coated fisetin nanoformulation in an experimental Alzheimer's disease (AD) model, focusing on improving fisetin's pharmacokinetics and exploring its impact on both brain and colon pathology.Materials & methods: AD was induced in mice by intracerebroventricular administration of Aβ_1-42. Mice were treated with either fisetin or a fisetin nanoformulation (5 mg/kg/day, orally) for 21 days. Behavioural assessments were conducted to evaluate memory impairment, motor deficits, and depression-like behaviour. Oxidative stress markers and pro-inflammatory cytokines were measured in the cortex, hippocampus and colon. The changes in cortical and hippocampal AChE levels were also recorded. Histological studies were performed on the cortex, hippocampus (dentate gyrus), and proximal colon.Results: The fisetin nanoformulation significantly improved neurobehavioral outcomes, reducing memory impairment, motor deficits and depression-like symptoms induced by Aβ_1-42. It also decreased oxidative and nitrosative stress, along with pro-inflammatory cytokine levels in the cortex, hippocampus and colon. Histological analyses revealed improved brain and colon tissue architecture after treatment with the nanoformulation.Conclusion: The chitosan-coated fisetin nanoformulation enhanced the neuroprotective effects of fisetin in an AD model, likely by improving its pharmacokinetic profile. The findings also suggest a potential link between colon health and Aβ-induced AD pathology, underscoring the therapeutic potential of fisetin nanoformulations in AD management.