The p75 neurotrophin receptor might mediate sepsis-induced synaptic and cognitive impairments
The p75 neurotrophin receptor might mediate sepsis-induced synaptic and cognitive impairments
复制标题
p75 神经营养素受体可能介导脓毒症引起的突触和认知障碍
DOI：
10.1016/j.bbr.2018.03.042
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发表时间：
2018-07-16
影响因子：
2.7
通讯作者：
Yang, Jianjun
中科院分区：
文献类型：
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作者：
Ji, Muhuo;Yuan, Hongmei;Yang, Jianjun
全身性炎症引起认知障碍，但在这一过程中涉及的机制尚不清楚。神经营养因子受体p75（p75（NTR））信号转导是导致许多神经退行性疾病中神经行为异常的关键病理因素。然而，p75（NTR）信号在脓毒症诱导的认知功能障碍的调节中的作用仍有待阐明。在这项研究中，通过盲肠结扎和穿孔（CLP）诱导全身炎症。神经行为的表现进行了评估，开放领域，新的物体识别，恐惧条件反射测试。通过酶联免疫吸附试验、蛋白质印迹分析和免疫荧光法测定海马中促炎细胞因子（肿瘤坏死因子（TNF-α）、白细胞介素-1 β（IL-1 β）、IL-6、IL-10）、凋亡标志物裂解型半胱天冬酶-3、离子钙结合接头分子1（IBA 1）、proBDNF、p75（NTR）、c-Jun N-末端激酶（JNK）和pJNK的表达。海马CA 1区的突触标记物通过高尔基体染色进行评估。在本研究中，我们发现全身性炎症诱导认知障碍，这是伴随着增加的表达的海马proBDNF和p75（NTR）。值得注意的是，我们发现，LM 11 A-31，一种口服的，血脑屏障渗透的小分子p75（NTR）信号转导调节剂，显着逆转脓毒症诱导的认知障碍，并恢复大多数异常的生化参数。总之，我们的研究表明proBDNF/p75（NTR）信号通路可能在脓毒症诱导的认知障碍的发展中起关键作用，而特异性p75（NTR）抑制剂可能为这种疾病和可能的其他神经退行性疾病提供新的治疗方法。
Systemic inflammation induces cognitive impairment, yet the mechanism involved in this process is unclear. Neurotrophin receptor p75 (p75(NTR)) signaling is a key pathological factor contributing to neurobehavioral abnormalities in many neurodegenerative diseases. However, the role of p75(NTR) signaling in the regulation of sepsis-induced cognitive impairment remains largely to be elucidated. In this study, systemic inflammation was induced by cecal ligation and puncture (CLP). Neurobehavioral performances were evaluated by open field, novel object recognition, and fear conditioning tests. The expressions of proinflammatory cytokines (tumor necrosis factor (TNF-alpha), interleukin-l beta (IL-1 beta), IL-6, IL-10), apoptosis marker cleaved caspase-3, ionized calcium binding adaptor molecule 1 (IBA1), proBDNF, p75(NTR), c-Jun N-terminal kinase (JNK), and pJNK in the hippocampus were determined by enzyme-linked immunosorbent assay, western blot analysis, and immunofluorescence. The synaptic marker in the CA1 region of the hippocampus was assessed by Golgi staining. In the present study, we showed that systemic inflammation induced cognitive impairment, which was accompanied by increased expressions of hippocampcal proBDNF and p75(NTR). Of note, we found that LM11A-31, an orally available, blood-brain barrier-permeant small-molecule p75(NTR) signaling modulator significantly reversed the sepsis-induced cognitive impairment and restored most of the abnormal biochemical parameters. Taken together, our study suggests that proBDNF/p75(NTR) signaling pathway might play a key role in the development of sepsis-induced cognitive impairment, whereas specific p75(NTR) inhibitor may provide a novel therapeutic approach for this disorder and possible other neurodegenerative diseases.