Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 191, Issue -, Pages 212-226Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2022.09.001
Keywords
Quercetin; Neuroprotective; Cognitive function; SIRT1; Nrf2; GPX4; Ferroptosis
Funding
- Affiliated Hospital of Jiangnan University
- Top Talent Support Program of Wuxi Health Committee [BJ2020042]
- Wuxi Key Medical Talents [ZDRC017]
- Postgraduate Research & Practice Innovation Program of Jiangsu Province [KYCX22_2434]
- University Qinglan Project of Jiangsu Province
- Fundamental Research Funds for the Central Universities [JUSRP221024]
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The study examined the protective effects of quercetin against seizure-induced neuron death and the mechanisms by which it alleviates cognitive function impairment through regulating the SIRT1/Nrf2/SLC7A11/GPX4 pathway.
Background: Epilepsy is one of the most common neurological disorders in childhood. However, classical anti -epileptic drugs are linked with drug toxicity and cognitive function impairment in children. Hence, it is essential to develop a novel therapy to solve this problem. Currently, studies indicate regulating the nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated ferroptosis pathway represents a potential advanced therapy for seizures. Hence, the present study aimed to explore whether quercetin, a natural polyphenol, could alleviate seizure-induced neuron death and preserve cognitive function by inhibiting Nrf2-mediated ferroptosis. Methods: Kainic acid-induced epileptic mice model, morris water maze (MWM) test, cell counting kit-8 (CCK-8) assays, western blotting analysis, enzyme-linked immunosorbent assay, flow cytometry, quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence staining, and RNA sequencing analysis were employed to explore the potential mechanisms by which quercetin exerts protective effects on seizure-induced neuron death in kainic acid-induced epileptic mice model and glutamate-induced HT22 neuronal cell death. Results: Our findings suggested the association between the Nrf2-mediated ferroptosis pathway and seizures in a clinical setting. Quercetin pretreatment alleviates seizure-like behaviors and cognitive impairment in KA-induced epileptic mice. Additionally, in vitro, co-treatment with quercetin effectively exerts neuroprotective effects in glutamate-induced HT22 neuronal cell death. These protective effects were also closely linked to regulating the Nrf2-mediated ferroptosis pathway. Furthermore, bioinformatic profiling revealed that the SIRT1/Nrf2/ SLC7A11/GPX4 pathway plays a crucial role in the Glu-induced HT22 cell death pretreated with quercetin. Conclusions: These findings indicated that quercetin effectively protects against seizure-induced neuron death in vivo and in vitro and alleviates cognitive function impairment via the SIRT1/Nrf2/SLC7A11/GPX4 pathway.
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