The citrus flavonoid “Nobiletin” impedes STZ-induced Alzheimer’s disease in a mouse model through regulating autophagy mastered by SIRT1/FoxO3a mechanism

The prominence of autophagy in the modulation of neurodegenerative disorders has sparked interest to investigate its stimulation in Alzheimer's disease (AD). Nobiletin possesses several bioactivities such as anti-inflammation, antioxidation, and neuroprotection. Consequently, the study's aim was to inspect the possible neurotherapeutic impact of Nobiletin in damping AD through autophagy regulation. Mice were randomly assigned into: Group I which received DMSO, Groups II, III, and IV obtained STZ (3 mg/kg) intracerebroventricularly once with Nobiletin (50 mg/kg/day; i.p.) in Group III and Nobiletin with EX-527 (2 mg/kg, i.p.) in Group IV. Interestingly, Nobiletin ameliorated STZ-induced AD through enhancing the motor performance and repressing memory defects. Moreover, Nobiletin de-escalated hippocampal acetylcholinesterase (AChE) activity and enhanced acetylcholine level while halting BACE1 and amyloid-β levels. Meanwhile, Nobiletin stimulated the autophagy process through activating the SIRT1/FoxO3a, LC3B-II, and ATG7 pathway. Additionally, Nobiletin inhibited Akt pathway and controlled the level of NF-κB and TNF-α. Nobiletin amended the oxidative stress through enhancing GSH and cutting down MDA levels. However, EX527, SIRT1 inhibitor, counteracted the neurotherapeutic effects of Nobiletin. Therefore, the present study provides a strong verification for the therapeutic influence of Nobiletin in AD. This outcome may be assigned to autophagy stimulation through SIRT1/FoxO3a, inhibiting AChE activity, reducing neuroinflammation and oxidative stress. GRAPHICAL ABSTRACT: [Image: see text]