Yueqi Yang’s research while affiliated with Liaocheng Teachers University and other places

Depression is the most common complication of childhood epilepsy, leading to a poor prognosis for seizure control and poor quality of life. However, the molecular mechanisms underlying epileptic depression have not been completely elucidated. Increasing evidence suggests that oxidative stress and neuroinflammation are major contributors to depression. The positive effects of dietary supplementation with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on depression have been previously reported. However, knowledge regarding the effects of EPA and DHA in managing depressive symptoms in pediatric patients with epilepsy is limited. Therefore, this study aims to investigate the effects of EPA and DHA on epileptic depression in a pentylenetetrazole (PTZ)-treated young mouse model. Three-week-old mice were fed a DHA- or EPA-enriched diet for 21 days and treated with PTZ (35 mg/kg, i.p.) every other day for a total of 10 times. EPA was more effective than DHA at alleviating PTZ-induced depressive symptoms. Pathological results revealed that DHA and EPA significantly improved neuronal degeneration in the hippocampus. Analysis of the mechanism revealed that DHA and EPA mitigated PTZ-induced myelin damage by increasing the protein levels of CNPase, Olig2, and MBP. Furthermore, both DHA and EPA reduced neuroinflammation by promoting microglial M2 polarization and suppressing the LCN2-NLRP3 inflammasome pathway. Notably, EPA polarized microglia towards the M2 phenotype. In addition, DHA and EPA decreased oxidative stress by inhibiting NOX2 and enhancing mitochondrial metabolism through the increased expression of mitochondrial respiratory chain complex I-V proteins. These findings suggest that DHA and EPA can be used as effective interventions to improve depression in children with epilepsy, with EPA being a particularly favorable option.

Epilepsy is a chronic neurological disorder that is more prevalent in children, and recurrent unprovoked seizures can lead to cognitive impairment. Numerous studies have reported the benefits of docosahexaenoic acid (DHA) on neurodevelopment and cognitive ability, while comparatively less attention has been given to eicosapentaenoic acid (EPA). Additionally, little is known about the effects and mechanisms of DHA and EPA in relation to seizure-induced cognitive impairment in the young rodent model. Current research indicates that ferroptosis is involved in epilepsy and cognitive deficiency in children. Further investigation is warranted to determine whether EPA or DHA can mitigate seizure-induced cognitive deficits by inhibiting ferroptosis. Therefore, this study was conducted to compare the effects of DHA and EPA on seizure-induced cognitive deficiency and reveal the underlying mechanisms focused on ferroptosis in a pentylenetetrazol (PTZ)-kindling young mice model. Mice were fed a diet containing DHA-enriched ethyl esters or EPA-enriched ethyl esters for 21 days at the age of 3 weeks and treated with PTZ (35 mg/kg, i.p.) every other day 10 times. The findings indicated that both EPA and DHA exhibited ameliorative effects on seizure-induced cognitive impairment, with EPA demonstrating a superior efficacy. Further mechanism study revealed that supplementation of DHA and EPA significantly increased cerebral DHA and EPA levels, balanced neurotransmitters, and inhibited ferroptosis by modulating iron homeostasis and reducing lipid peroxide accumulation in the hippocampus through activating the Nrf2/Sirt3 signal pathway. Notably, EPA exhibited better an advantage in ameliorating iron dyshomeostasis compared to DHA, owing to its stronger upregulation of Sirt3. These results indicate that DHA and EPA can efficaciously alleviate seizure-induced cognitive deficiency by inhibiting ferroptosis in PTZ-kindled young mice.

Mol. Nutr. Food Res. 2022, 66, 2200275 DOI: 10.1002/mnfr.202200275 Dietary supplementation of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) suppressed iron dyshomeostasis, oxidative stress and neuroinflammation in PTZ-induced kindling model mice. DHA and EPA are demonstrated to regulate the Nrf2 signaling and inhibit NLRP3 inflammasome activation via different mode-of-actions, implying great and different potential in the prevention and treatment of epilepsy. This is reported by Min Wen and co-workers in article number 2200275.

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.

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 are still unclarified. This study aimed 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 inhibited PTZ-induced seizures and depressive-like behavior, whereas EPA outcompetes DHA. Further mechanistic studies revealed 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). We found that DHA and EPA comparably inhibited NLRP3 inflammasome activation but with different mode-of-actions: EPA preferred to inhibit the binding of NLRP3 and ASC, while DHA decreased the protein levels of ASC and Caspase-1. Conclusions: These results indicated that DHA and EPA could efficaciously alleviate PTZ-induced seizure and depressive-like behavior but with different efficiency and molecular mechanisms. This article is protected by copyright. All rights reserved.

The 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. An emerging study indicated that ferroptosis plays an important role in neurologic diseases but has been rarely reported in chronic SD. Here, we investigated the prophylactic effects of a medium-chain triglyceride-enriched KD (MKD) and a long-chain triglyceride-enriched KD (LKD) on cognitive deficiency and revealed the underlying mechanism focused on ferroptosis in chronic SD model mice. The results showed that the MKD exhibited stronger effects than the LKD on improving cognitive deficiency via suppressing ferroptosis and improving synaptic plasticity. Further mechanism results indicated that MKD produced higher Sirt3 protein levels than LKD, which probably contributed to the synergistic effect of beta hydroxybutyric acid and decanoic acid. Our finds provide novel evidence for the KD as a safe and feasible dietary intervention to prevent chronic SD-induced cognitive deficiency, and suggest a better choice of medium-chain fatty acid-enriched KD.