Huang Ailing, Chen Yang, Wang Shaoshuang, Du Hailiang, Guan Ao, Wu Huanghui, Zhai Qian, Duan Na, Li Xuying, Zhao Pin, Zhu Yulin, Bai Juan, Xiao Ye, Yang Tingting, Wang Qiang, Deng Bin
Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; School of Medicine, Xiamen University, Xiamen, China.
Department of Neurology, The 904th Hospital of PLA, Medical School of Anhui Medical University, Wuxi, China.
Eur J Pharmacol. 2023 May 15;947:175667. doi: 10.1016/j.ejphar.2023.175667. Epub 2023 Mar 28.
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.
中风后焦虑（PSA）是一种中风后发生的情感障碍，以焦虑为主要临床表现。PSA的发病机制尚不清楚，预防和治疗措施也很少。我们之前的研究发现，HDAC3可通过介导p65去乙酰化激活NF-κB信号通路，进而影响小胶质细胞的激活。这意味着HDAC3可能是缺血性中风小鼠中的关键介质，并调节对应激的焦虑易感性。本研究通过光血栓性中风联合慢性束缚应激在雄性C57BL/6小鼠中建立了PSA模型。我们重点探讨给予艾司氯胺酮是否能减轻焦虑样行为和神经炎症，这可能与抑制HDAC3表达和NF-κB通路激活有关。结果显示，给予艾司氯胺酮可减轻PSA小鼠的焦虑样行为。并且结果显示，艾司氯胺酮可减轻皮质小胶质细胞的激活，改变小胶质细胞数量，并保持形态特征。此外，结果显示，在给予艾司氯胺酮治疗的PSA小鼠中，HDAC3、磷酸化p65/p65和COX1的表达显著降低。此外，我们还发现艾司氯胺酮降低了PGE2的表达，PGE2是负面情绪的主要调节因子之一。有趣的是，我们的结果表明，艾司氯胺酮在PSA的病理过程中减少了神经元周围网（PNN）的数量。总之，本研究表明，艾司氯胺酮可减轻小胶质细胞的激活，减少炎性细胞因子，并抑制PSA小鼠皮质中HDAC3和NF-κB的表达，以减轻焦虑样行为。我们的结果为将艾司氯胺酮应用于PSA提供了一个新的潜在治疗靶点。
