PDF(Pubmed)
Abstract：
There is an intrinsic relationship between psychiatric disorders and neuroinflammation, including bipolar disorder. Ouabain, an inhibitor of Na+/K+-ATPase, has been implicated in the mouse model with manic-like behavior. However, the molecular mechanisms linking neuroinflammation and manic-like behavior require further investigation. CCAAT/Enhancer-Binding Protein Delta (CEBPD) is an inflammatory transcription factor that contributes to neurological disease progression. In this study, we demonstrated that the expression of CEBPD in astrocytes was increased in ouabain-treated mice. Furthermore, we observed an increase in the expression and transcript levels of CEBPD in human primary astrocytes following ouabain treatment. Transcriptome analysis revealed high MMP8 expression in human primary astrocytes following CEBPD overexpression and ouabain treatment. We confirmed that MMP8 is a CEBPD-regulated gene that mediates ouabain-induced neuroinflammation. In our animal model, treatment of ouabain-injected mice with M8I (an inhibitor of MMP8) resulted in the inhibition of manic-like behavior compared to ouabain-injected mice that were not treated with M8I. Additionally, the reduction in the activation of astrocytes and microglia was observed, particularly in the hippocampal CA1 region. Excessive reactive oxygen species formation was observed in ouabain-injected mice, and treating these mice with M8I resulted in the reduction of oxidative stress, as indicated by nitrotyrosine staining. These findings suggest that MMP8 inhibitors may serve as therapeutic agents in mitigating manic symptoms in bipolar disorder.
摘要：
精神疾病和神经炎症之间存在内在联系,包括躁郁症.Ouabain,Na+/K+-ATP酶的抑制剂，与躁狂样行为的小鼠模型有关。然而,神经炎症和躁狂样行为的分子机制需要进一步研究.CCAAT/增强子结合蛋白Δ（CEBPD）是一种炎性转录因子，有助于神经系统疾病的进展。在这项研究中,我们证明，在哇巴因治疗的小鼠中，CEBPD在星形胶质细胞中的表达增加。此外，我们观察到在哇巴因治疗后,CEBPD在人原代星形胶质细胞中的表达和转录水平增加.转录组分析显示，在CEBPD过表达和哇巴因治疗后，人原代星形胶质细胞中MMP8的高表达。我们证实MMP8是CEBPD调节的基因，可介导哇巴因诱导的神经炎症。在我们的动物模型中,与未用M8I治疗的哇巴因注射的小鼠相比，用M8I（MMP8的抑制剂）治疗哇巴因注射的小鼠会抑制躁狂样行为。此外,观察到星形胶质细胞和小胶质细胞的活化减少，特别是在海马CA1区。在注射乌巴因的小鼠中观察到过量的活性氧形成，用M8I治疗这些小鼠可以减少氧化应激，如硝基酪氨酸染色所示。这些发现表明MMP8抑制剂可以作为缓解双相情感障碍躁狂症状的治疗剂。
