Hippocampal CA1 CaMKII mediates neuroinflammatory responses via COX-2/PGE2 signaling pathways in depression
Hippocampal CA1 CaMKII mediates neuroinflammatory responses via COX-2/PGE2 signaling pathways in depression
复制标题
海马 CA1 βCaMKII 通过 COX-2/PGE2 信号通路介导抑郁症的神经炎症反应
DOI：
10.1186/s12974-018-1377-0
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发表时间：
2018-12-08
影响因子：
9.3
通讯作者：
Yu, Shu Yan
中科院分区：
文献类型：
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作者：
Song, Qiqi;Fan, Cuiqin;Yu, Shu Yan
背景神经炎症最近被认为是抑郁症病理生理学中的一个重要危险因素。然而，潜在的分子机制和新治疗策略的发展作为靶向这些炎症途径用于治疗抑郁症的手段仍未得到解决。在本研究中，我们旨在研究神经炎症与抑郁样行为诱导相关的分子事件。方法采用慢性不可预测轻度应激（CUMS）或脂多糖（LPS）诱导大鼠抑郁样行为。采用RT-PCR、免疫印迹和免疫荧光法对炎症因子及相关蛋白进行验证。在大鼠脑内注射腺病毒相关病毒（AAV）可过表达或阻断钙/钙调素依赖性蛋白激酶II型（CaMKII）的功能。采用体内脑室注射SB203580阻断p38丝裂原活化蛋白激酶（MAPK）。最后采用酶联检测试剂盒检测前列腺素E2 （PGE2）浓度。结果抑郁症大鼠CA1海马区环加氧酶(COX)-2表达升高，COX -2参与促炎因子PGE2的生成，从而激活神经胶质细胞。此外，抑郁症大鼠CA1中的CaMKII显著上调，而抗抑郁药物治疗下调了该激酶。通过将构建的AAV-CaMKII注入CA1区域，CaMKII过表达导致p38 MAPK和激活转录因子2 （ATF2）的磷酸化。这些影响伴随着COX-2/PGE2通路活性的增强，并有效地诱导了抑郁症的核心症状。相反，CA1区域内CaMKII的敲低逆转了这些炎症相关的生化参数，并显著挽救了抑郁症状。这些结果表明，CaMKII可以通过激活CA1区域的神经炎症通路，在抑郁症中发挥关键的调节作用。此外，本研究还为今后抑郁症治疗的分子靶点和药物治疗研究提供了新的视角。
BackgroundNeuroinflammation has recently emerged as a critical risk factor in the pathophysiology of depression. However, the underlying molecular mechanisms and the development of novel therapeutic strategies as means to target these inflammatory pathways for use in the treatment of depression remain unresolved. In the present study, we aimed to investigate the molecular events of neuroinflammation as related to its induction of depression-like behaviors.MethodsChronic unpredictable mild stress (CUMS) or lipopolysaccharide (LPS) was used to induce depression-like behaviors in rats. The inflammatory factors and related proteins were verified by RT-PCR, immunoblotting, and immunofluorescence assay. In vivo intracerebral injection of adenovirus-associated virus (AAV) in rats was used to overexpress or block the function of the form of the calcium/calmodulin-dependent protein kinase type II (CaMKII). In vivo intracerebroventricular injection of SB203580 was used to block p38 mitogen-activated protein kinase (MAPK). Finally, the prostaglandin E2 (PGE2) concentration was verified by using enzyme-linked assay kit.ResultsThe expression of cyclo-oxygenase (COX)-2, which is responsible for production of the pro-inflammatory factor PGE2 and thus glial activation, was increased in the CA1 hippocampus in a rat model of depression. Further, the CaMKII in CA1 was significantly upregulated in depressed rats, while antidepressant treatment downregulated this kinase. Overexpression of CaMKII via infusion of a constructed AAV-CaMKII into the CA1 region resulted in phosphorylation of the p38 MAPK and the activating transcription factor 2 (ATF2). These effects were accompanied by an enhanced activity of the COX-2/PGE2 pathway and effectively induced core symptoms of depression. Conversely, knockdown of CaMKII within the CA1 region reversed these inflammation-related biochemical parameters and significantly rescued depression symptoms.ConclusionThese results demonstrate that CaMKII can act as a critical regulator in depression via activating neuroinflammatory pathways within the CA1 region. Moreover, this study provides new perspectives on molecular targets and drug therapies for future investigation in the treatment of depression.