Sleep deprivation (SD) is one of the main risk factors for Alzheimer’s disease (AD), but the underlying mechanism is still unclear. Ketogenic diet (KD) has been shown widely neuroprotective effects but less known about its effect on SD-induced AD. In the present study, a continuous 21 days SD mouse model with or without KD was established. The changes of cognitive function, pathological hallmarks of AD, ferroptosis, and intracellular signal pathways in mice were detected by Morris water maze, ThS staining, diaminobenzidine (DAB)-enhanced Perls’ stain, antioxidant assay, immuno-histochemistry, and western blot. The results showed that KD can prevent the cognitive deficiency, amyloid deposition and hyperphosphorylated tau induced by chronic SD. Analysis of ferroptosis revealed that KD can inhibit iron dyshomeostasis by down-regulating the expression of TfR1 and DMT1 and up-regulating the expression of FTH1, FPN1. Meanwhile, KD alleviated oxidative stress with elevated xCT/GPX4 axis, FSP1 and reduced MDA. In addition, KD could promote neuronal repair by enhancing BDNF and DCX. Further studies demonstrated that KD activated Sirt1/Nrf2 signaling pathway in the hippocampus in SD-exposed mice. Our finding firstly suggested that KD could prevent chronic SD-induced AD by inhibiting ferroptosis and improving the neuronal repair ability via Sirt1/Nrf2 signaling pathway.

Ketogenic diet (KD) is well known for its neuroprotective effect, but little is known about its prophylactic efficacy against chronic sleep deprivation (SD) induced cognitive deficiency. Emerging study indicated that...

Scope: It has been reported that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anticonvulsant effects, yet the respective mechanism of EPA and DHA on epilepsy is still unclarified. This study aims to investigate the effect of EPA and DHA on pentylenetetrazol (PTZ) induced seizures and depression. Methods and results: The administration of EPA and DHA at a dose of 1% w/w significantly inhibits PTZ-induced seizures and depressive-like behavior, whereas EPA outcompetes DHA. Further mechanistic studies reveal that the higher effect of EPA can be partly attributed to the promotion of M2 polarization, inhibition of M1 polarization of microglia, and lower iron content in the brain, resulting from the stronger activation of nuclear factor E2-related factor 2 (Nrf2). This study finds that DHA and EPA comparably inhibit NLRP3 inflammasome activation but with different mode-of-actions: EPA prefers to inhibit the binding of NLRP3 and ASC, while DHA decreases the protein levels of ASC and Caspase-1. Conclusions: These results indicate that DHA and EPA can efficaciously alleviate PTZ-induced seizure and depressive-like behavior but with different efficiency and molecular mechanisms.