Previous studies have demonstrated a close association between an altered immune system and major depressive disorders, and inhibition of neuroinflammation may represent an alternative mechanism to treat depression. Recently, the anti-inflammatory activity of ibrutinib has been reported. However, the effect of ibrutinib on neuroinflammation-induced depression and its underlying mechanism has not been comprehensively studied. Therefore, we aimed to elucidate the potential anti-depressive role and mechanism of ibrutinib against neuroinflammation-induced depression and synaptic defects. Our results showed that ibrutinib treatment significantly reduced lipopolysaccharide (LPS)-induced depressive-like behaviors and neuroinflammation via inhibiting NF-kB activation, decreasing proinflammatory cytokine levels, and normalizing redox signaling and its downstream components, including Nrf2, HO-1, and SOD2, as well as glial cell activation markers, such as Iba-1 and GFAP. Further, ibrutinib treatment inhibited LPS-activated inflammasome activation by targeting NLRP3/P38/Caspase-1 signaling. Interestingly, LPS reduced the number of dendritic spines and expression of BDNF, and synaptic-related markers, including PSD95, snap25, and synaptophysin, were improved by ibrutinib treatment in the hippocampal area of the mouse brain. In conclusion, our findings suggest that ibrutinib can alleviate neuroinflammation and synaptic defects, suggesting it has antidepressant potential against LPS-induced neuroinflammation and depression.

中文翻译：

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依鲁替尼减轻抑郁症小鼠模型中 LPS 诱导的神经炎症和突触缺陷

先前的研究表明，免疫系统改变与重度抑郁症之间存在密切关联，抑制神经炎症可能代表了治疗抑郁症的另一种机制。最近，已经报道了依鲁替尼的抗炎活性。然而，依鲁替尼对神经炎症诱导的抑郁症的影响及其潜在机制尚未得到全面研究。因此，我们旨在阐明依鲁替尼对神经炎症诱导的抑郁和突触缺陷的潜在抗抑郁作用和机制。我们的结果表明，依鲁替尼治疗通过抑制 NF-kB 活化，降低促炎细胞因子水平，显着减少脂多糖 (LPS) 诱导的抑郁样行为和神经炎症，并使氧化还原信号及其下游组分正常化，包括 Nrf2、HO-1 和 SOD2，以及神经胶质细胞活化标记物，如 Iba-1 和 GFAP。此外，依鲁替尼治疗通过靶向 NLRP3/P38/Caspase-1 信号传导抑制 LPS 激活的炎性体激活。有趣的是，LPS 减少了树突棘的数量和 BDNF 的表达，并且通过依鲁替尼治疗小鼠大脑海马区的突触相关标志物，包括 PSD95、snap25 和突触素，得到了改善。总之，我们的研究结果表明，依鲁替尼可以减轻神经炎症和突触缺陷，表明它具有对抗 LPS 诱导的神经炎症和抑郁症的抗抑郁潜力。依鲁替尼治疗通过靶向 NLRP3/P38/Caspase-1 信号传导抑制 LPS 激活的炎症小体激活。有趣的是，LPS 减少了树突棘的数量和 BDNF 的表达，并且通过依鲁替尼治疗小鼠大脑海马区的突触相关标志物，包括 PSD95、snap25 和突触素，得到了改善。总之，我们的研究结果表明，依鲁替尼可以减轻神经炎症和突触缺陷，表明它具有对抗 LPS 诱导的神经炎症和抑郁症的抗抑郁潜力。依鲁替尼治疗通过靶向 NLRP3/P38/Caspase-1 信号传导抑制 LPS 激活的炎症小体激活。有趣的是，LPS 减少了树突棘的数量和 BDNF 的表达，并且通过依鲁替尼治疗小鼠大脑海马区的突触相关标志物，包括 PSD95、snap25 和突触素，得到了改善。总之，我们的研究结果表明，依鲁替尼可以减轻神经炎症和突触缺陷，表明它具有对抗 LPS 诱导的神经炎症和抑郁症的抗抑郁潜力。在小鼠大脑的海马区通过依鲁替尼治疗得到改善。总之，我们的研究结果表明，依鲁替尼可以减轻神经炎症和突触缺陷，表明它具有对抗 LPS 诱导的神经炎症和抑郁症的抗抑郁潜力。在小鼠大脑的海马区通过依鲁替尼治疗得到改善。总之，我们的研究结果表明，依鲁替尼可以减轻神经炎症和突触缺陷，表明它具有对抗 LPS 诱导的神经炎症和抑郁症的抗抑郁潜力。