Nuclear factor erythroid 2-related factor improves depression and cognitive dysfunction in rats with ischemic stroke by mediating wolfram syndrome 1

Objective: This research aims to investigate the molecular mechanism of nuclear factor erythroid 2-related factor (Nrf2) in improving post-stroke depression and cognitive impairment (PSDCI) by mediating wolfram syndrome 1 (Wfs1). Methods: PSDCI rat model was established through middle cerebral artery occlusion (MCAO) and chronic unpredictable mild stress (CUMS). Dimethyl fumarate (DMF) was utilized as an Nrf2 activator, while Wfs1 knockdown lentiviral plasmid was injected into rats for functional investigations. Cognitive function-and depression-relevant parameters were assessed using Morris water maze, forced swimming, sucrose preference, modified neurological severity score (mNSS) tests. The infarct size, pathological changes, and neuronal damage were also evaluated. Additionally, oxidative stress-and inflammatory response-associated proteins were detected by enzyme-linked immunosorbent assay. The binding relation between Nrf2 and the Wfs1 promoter region was analyzed and verified by dual-luciferase and chromatin immunoprecipitation assays. Results: PSDCI rats had reduced Nrf2 and Wfs1 expression in the hippocampal tissue and inhibited nuclear translocation of Nrf2, showing aggravated oxidative stress and inflammatory responses as well as cognitive dysfunction-and depressive-like symptoms. However, these symptoms in PSDCI rats can be alleviated in response to Nrf2 activation. Furthermore, Nrf2 activation increased the enrichment level of Nrf2 in the Wfs1 promoter region, promoting the transcriptional expression of Wfs1. Wfs1 knockdown partly reversed the effect of Nrf2 activation on the neuronal damage, cognitive dysfunction-and depressive-like symptoms of PSDCI rats. Conclusion: Nrf2 activation can promote Wfs1 expression to reduce neuroinflammation and oxidative stress responses, ultimately alleviating PSDCI in rats.