Esketamine ameliorates post-stroke anxiety by modulating microglial HDAC3/NF-κB/COX1 inflammatory signaling in ischemic cortex.
Ailing Huang, Yang Chen, Shaoshuang Wang, Hailiang Du, Ao Guan, Huanghui Wu, Qian Zhai, Na Duan, Xuying Li, Pin Zhao, Yulin Zhu, Juan Bai, Ye Xiao, Tingting Yang, Qiang Wang, Bin Deng
European Journal of Pharmacology March 28, 2023 DOI: 10.1016/j.ejphar.2023.175667 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Male C57BL/6 mice with photothrombotic stroke combined with chronic restraint stress (post-stroke anxiety model) |
| Intervention | Esketamine |
| Topics | Anxiety Esketamine Ketamine |
| Keywords | Microglia Animals Mice, inbred c57bl Nf-kappa b Male Neuroinflammation Histone deacetylases Perineuronal net Post-stroke anxiety |
| Key findings | Esketamine administration alleviated anxiety-like behavior in post-stroke anxiety mice and reduced cortical microglial activation, inflammatory markers (COX1, PGE2), HDAC3 expression, phospho-p65/p65, and perineuronal net number. The authors suggest these effects reflect inhibition of HDAC3 and NF-κB signaling, proposing HDAC3 as a potential therapeutic target for post-stroke anxiety. |
Abstract
Post-stroke anxiety (PSA) is a kind of affective disorder occurring after a stroke, with anxiety as the primary clinical manifestation. PSA's mechanism is unclear, and there are few prevention and treatment measures. Our previous study found that HDAC3 could activate NF-κB signaling through mediated p65 deacetylation, which further influenced microglia activation. That implies HDAC3 may be the key mediator in ischemic stroke mice and modulates anxiety susceptibility to stress. This study established a PSA model in male C57BL/6 mice through photothrombotic stroke combined with chronic restrain stress. We focused on exploring whether esketamine administration can alleviate anxiety-like behavior and neuroinflammation, which may be associated with inhibiting HDAC3 expression and NF-κB pathway activation. The results showed that esketamine administration alleviated anxiety-like behavior in PSA mice. And the results showed that esketamine alleviated cortical microglial activation, altered microglial number, and kept morphology features. Furthermore, the results showed that the expression of HDAC3, phosphor-p65/p65, and COX1 significantly decreased in esketamine-treated PSA mice. Besides, we also found that esketamine reduced PGE2 expression, one of the primary regulators of negative emotions. Interestingly, our results indicate that esketamine reduced the perineuronal net (PNN) number in the pathological process of PSA. In conclusion, this study suggests esketamine could alleviate microglial activation, reduces inflammatory cytokine, and inhibits the expression of HDAC3 and NF-κB in the cortex of PSA mice to attenuate anxiety-like behavior. Our results provided a new potential therapeutic target for applying esketamine to PSA.
Comparable studies
Other preclinical and animal studies on esketamine for anxiety, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| N,N-dimethyltryptamine elicits antidepressant and anxiolytic effects in helpless mice: a comparative study with S-ketamine. Male helpless mice (single-housed and group-housed) | 2026 | Animal study | |
| Esketamine alleviates trigeminal neuralgia and anxiety-like behaviors in mice by inhibiting RIPK1/RIPK3/MLKL-mediated necroptosis. Mice with partial infraorbital nerve transection (pIONT) | 2026 | Animal study | |
| S-ketamine mitigates paclitaxel-induced pain-related anxiety-like behavior through downregulation of mGluR5 and activation of the BDNF/TrkB signaling pathway Mice with paclitaxel-induced peripheral neuropathy | 2026 | Preclinical experimental study | |
| S-Ketamine Pretreatment Alleviates Anxiety-Like Behaviors and Mechanical Allodynia and Blocks the Pro-inflammatory Response in Striatum and Periaqueductal Gray From a Post-traumatic Stress Disorder Model Adult male rats exposed to single-prolonged stress (SPS) model of PTSD | 2022 | Animal study |