Fluoxetine Alleviates Vascular Cognitive Impairment by Activating the Nrf2/ARE Pathway via Sp1-Mediated OTUD1 Transcription.

Abstract

PURPOSE: The research focused on investigating the influence of fluoxetine on cognitive dysfunction associated with cerebral small vessel disease (CSVD). METHODS: An oxygen-glucose deprivation and reoxygenation (OGD/R) HT22 (mouse hippocampal neuronal cell) cell model was created to detect apoptosis, inflammatory factors, and oxidative stress marker levels. A CSVD rat model was established using bilateral common carotid artery occlusion. After being treated with fluoxetine, cognitive impairment, neuronal damage, oxidative stress, and inflammatory factors were assessed in the CSVD rats. RESULTS: Fluoxetine treatment significantly ameliorated memory, spatial learning, recognition index, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and the levels of Nrf2, heme oxygenase-1 (HO-1), and quinone oxidoreductase-1 (NQO-1) in CSVD rats. Fluoxetine reduced hippocampal cell apoptosis rate, pro-apoptotic proteins (Bax and cleaved caspase-3), and proinflammatory factors (TNF-α and IL-1β). Concurrently, it mitigated oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), and reactive oxygen species (ROS). Notably, fluoxetine upregulated the levels of anti-inflammatory cytokine IL-10. Mechanistically, fluoxetine activated the Nrf2/ARE pathway by inhibiting Nrf2 ubiquitination. In addition, fluoxetine promotes OTU domain-containing protein 1 (OTUD1) transcription by activating Sp1, and the OTUD1 knockdown reversed the activation of the Nrf2/ARE pathway by fluoxetine. CONCLUSION: Fluoxetine alleviates CSVD-related cognitive impairment via the Sp1-mediated upregulation of OTUD1 to activate the Nrf2/ARE pathway. This study indicates fluoxetine may have therapeutic potential for CSVD-related cognitive impairment.

Key Findings

• Fluoxetine treatment improved memory, spatial learning, and recognition in a CSVD rat model.
• Fluoxetine increased antioxidant enzyme levels (SOD, GSH-Px) and Nrf2 pathway components (Nrf2, HO-1, NQO-1).
• Fluoxetine reduced apoptosis, proinflammatory factors (TNF-α, IL-1β), and oxidative stress markers (8-OHdG, MDA, ROS) while upregulating anti-inflammatory cytokine IL-10.
• Mechanistically, fluoxetine activated the Nrf2/ARE pathway by inhibiting Nrf2 ubiquitination and promoting OTUD1 transcription via Sp1 activation.

Clinical Significance

Citation

Wan Qi, Hao Jingwen, Chen Chanjuan. Fluoxetine Alleviates Vascular Cognitive Impairment by Activating the Nrf2/ARE Pathway via Sp1-Mediated OTUD1 Transcription. Free radical research. 2026-Apr-13.