Esketamine ameliorates post-stroke anxiety by modulating microglial HDAC3/NF-?B/COX1 inflammatory signaling in ischemic cortex

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-kappa B 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-kappa B 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-kappa B in the cortex of PSA mice to attenuate anxiety-like behavior. Our results provided a new potential ther-apeutic target for applying esketamine to PSA.

Automated summary

In this study, a post-stroke anxiety (PSA) model was established in male C57BL/6 mice and esketamine was administered to alleviate anxiety-like behavior. Esketamine was found to reduce microglial activation, inflammatory cytokine expression, and the expression of HDAC3 and NF-kappa B in the cortex of PSA mice. These findings provide a potential therapeutic target for treating post-stroke anxiety.