Deans' stroke musings: Fluoxetine Alleviates Vascular Cognitive Impairment by Activating the Nrf2/ARE Pathway via Sp1-Mediated OTUD1 Transcription

Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

Friday, April 17, 2026

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

Your doctor is familiar with why fluoxetine is not recommended for stroke, right?

fluoxetine (24 posts to May 2014)

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

Qi Wan

Jingwen Hao

Received 23 Jan 2026, Accepted 31 Mar 2026, Accepted author version posted online: 13 Apr 2026

https://doi.org/10.1080/10715762.2026.2658796

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.