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Nrf2 Alleviates Cognitive Dysfunction and Brain Inflammatory Injury via Mediating Wfs1 in Rats with Depression-Like Behaviors

Abstract—

Depression is a major threat to global mental health and demands targeted therapeutic regimens. The current study set out to evaluate the regulatory mechanism of nuclear factor erythroid-2 related factor 2 (Nrf2) in depression-induced cognitive dysfunction and inflammatory injury. First, depressive rat models were established via chronic unpredicted mild stress (CUMS) treatment. Cognitive function of rats was assessed by a series of behavioral tests. Rats were further stereotactically injected with Nrf2 overexpression vector, with expression patterns of Nrf2, miR-17-5p, and wolfram syndrome 1 (Wfs1) detected using qRT-PCR and Western blot assay. In addition, pathological changes of murine hippocampus were analyzed using hematoxylin–eosin staining. In vitro cell models were additionally established using lipopolysaccharide. Cell viability was detected via the CCK-8 method. Moreover, levels of TNF-α, IL-1β, and IL-10 were detected via ELISA. Furthermore, the binding relationships between Nrf2 and the miR-17-5p promoter, miR-17-5p, and Wfs1 were verified. It was found that Nrf2 was weakly expressed in CUMS-treated rats, whereas Nrf2 upregulation alleviated cognitive dysfunction and brain inflammatory injury. Meanwhile, Nrf2 inhibited miR-17-5p expression via binding to the miR-17-5p promoter. miR-17-5p was also found to limit Wfs1 transcription. miR-17-5p overexpression or Wfs1 downregulation partly reversed the role of Nrf2 in reliving inflammatory injury of murine hippocampal neurons. Overall, our findings indicated that Nrf2 inhibited miR-17-5p expression and promoted Wfs1 transcription, thereby alleviating cognitive dysfunction and inflammatory injury in rats with depression-like behaviors.

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X. H—conceptualization, methodology, software. Q. Q—data curation, writing (original draft preparation). D. R—writing (reviewing and editing).

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Correspondence to Xuezhu Huang.

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The animal experiment followed the Guidelines for the Use and Management of Laboratory Animals and was approved by the Laboratory Animal Ethics Committee of Wenzhou Medical University.

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Huang, X., Qu, Q. & Ren, D. Nrf2 Alleviates Cognitive Dysfunction and Brain Inflammatory Injury via Mediating Wfs1 in Rats with Depression-Like Behaviors. Inflammation 45, 399–413 (2022). https://doi.org/10.1007/s10753-021-01554-4

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  • DOI: https://doi.org/10.1007/s10753-021-01554-4

KEY WORDS

  • Depression; Nrf2; miR-17-5p; Wfs1; cognitive dysfunction; inflammatory injury; CUMS; inflammatory cytokine.