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Nrf2 Alleviates Cognitive Dysfunction and Brain Inflammatory Injury via Mediating Wfs1 in Rats with Depression-Like
Xuezhu Huang1,2,3,1, Qing Qu4, Dongmei Ren4
1Mental Medicine College of Wenzhou Medical University, No. 82, Xueyuan Xilu, Lucheng District, Wenzhou, 325000, Zhejiang, China. drhxzwz@163.com.
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.
Insights
Nuclear factor erythroid-2 related factor 2 (Nrf2) upregulation alleviates depression-induced cognitive dysfunction and inflammation by inhibiting miR-17-5p and promoting Wfs1 transcription. This pathway offers a potential therapeutic target for mental health disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Depression poses a significant global mental health challenge, necessitating novel therapeutic strategies.
- Understanding the molecular mechanisms underlying depression-induced cognitive deficits and neuroinflammation is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the regulatory role of nuclear factor erythroid-2 related factor 2 (Nrf2) in depression-associated cognitive dysfunction and inflammatory injury.
- To elucidate the molecular interactions between Nrf2, miR-17-5p, and Wolfram syndrome 1 (Wfs1) in the context of depression.
Main Methods:
- Establishment of a chronic unpredictable mild stress (CUMS) rat model to induce depression-like behaviors and cognitive impairment.
- Assessment of cognitive function using behavioral tests and hippocampal pathology via hematoxylin-eosin staining.
- In vitro studies using lipopolysaccharide-induced cell models to evaluate cell viability and inflammatory markers (TNF-α, IL-1β, IL-10) via CCK-8 and ELISA assays.
- Analysis of Nrf2, miR-17-5p, and Wfs1 expression using qRT-PCR and Western blot, with verification of binding interactions.
Main Results:
- Nrf2 expression was reduced in CUMS-treated rats; Nrf2 upregulation ameliorated cognitive deficits and neuroinflammation.
- Nrf2 inhibited miR-17-5p expression by binding to its promoter, and miR-17-5p suppressed Wfs1 transcription.
- Overexpression of miR-17-5p or downregulation of Wfs1 partially reversed the protective effects of Nrf2 on hippocampal neurons.
Conclusions:
- Nrf2 plays a protective role in depression-like behaviors by modulating the miR-17-5p/Wfs1 axis.
- The Nrf2-mediated inhibition of miR-17-5p and subsequent promotion of Wfs1 transcription represent a key mechanism alleviating cognitive dysfunction and neuroinflammation in depression.
