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Fluoxetine alleviates vascular cognitive impairment by activating the Nrf2/ARE pathway via Sp1-mediated OTUD1

Qi Wan1, Jingwen Hao1, Chanjuan Chen1

  • 1Department of Neurology, First Hospital of Changsha, Changsha, China.

Free Radical Research
|April 13, 2026
PubMed

Insights

Fluoxetine improves cognitive function in cerebral small vessel disease (CSVD) by reducing neuronal damage and inflammation. It activates the Nrf2/ARE pathway through OTUD1, suggesting therapeutic potential for CSVD-related cognitive impairment.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Cell Biology

Background:

  • Cerebral small vessel disease (CSVD) is a common cause of cognitive impairment.
  • Current treatments for CSVD-related cognitive dysfunction are limited.
  • Understanding the molecular mechanisms underlying CSVD is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the therapeutic effects of fluoxetine on cognitive dysfunction in a rat model of CSVD.
  • To elucidate the molecular mechanisms by which fluoxetine exerts its effects on CSVD-related cognitive impairment.

Main Methods:

  • Established a CSVD rat model using bilateral common carotid artery occlusion.
  • Utilized an oxygen-glucose deprivation and reoxygenation (OGD/R) HT22 cell model to assess cellular responses.
  • Administered fluoxetine to CSVD rats and evaluated cognitive function, neuronal damage, oxidative stress, and inflammatory markers.

Main Results:

  • Fluoxetine treatment significantly improved memory and spatial learning in CSVD rats.
  • Fluoxetine reduced hippocampal cell apoptosis, oxidative stress (measured by SOD, GSH-Px, 8-OHdG, MDA, ROS), and inflammation (measured by TNF-α, IL-1β).
  • Fluoxetine activated the Nrf2/ARE pathway by upregulating OTUD1 via Sp1, which was reversed by OTUD1 knockdown.

Conclusions:

  • Fluoxetine alleviates CSVD-related cognitive impairment by activating the Nrf2/ARE pathway through Sp1-mediated OTUD1 upregulation.
  • This study highlights the potential of fluoxetine as a therapeutic agent for cognitive deficits associated with CSVD.
Keywords:
FluoxetineNrf2/AREcerebral small vessel diseasecognitive dysfunctionneuronal apoptosis

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