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GLP-1R activation ameliorated novel-object recognition memory dysfunction via regulating hippocampal AMPK/NF-κB pathway in neuropathic pain mice
Neurobiology of Learning and Memory ( IF 2.7 ) Pub Date : 2021-05-18 , DOI: 10.1016/j.nlm.2021.107463
Long-Qing Zhang 1 , Wen Zhang 1 , Ting Li 1 , Ting Yang 1 , Xiaoman Yuan 1 , Yaqun Zhou 1 , Qian Zou 2 , Hui Yang 1 , Feng Gao 1 , YuKe Tian 1 , Wei Mei 1 , Xue-Bi Tian 1
Affiliation  

Growing evidences indicate that neuropathic pain is frequently accompanied with cognitive impairments, which aggravate the decrease in the quality of life of chronic pain patients. Furthermore, it has been shown that the activation of Glucagon-like-peptide-1receptor (GLP-1R) improved memory deficit in multiple diseases, including Alzheimer’s disease (AD), stroke. However, whether GLP-1R activation could improve memory impairment induced by neuropathic pain and the mechanisms underlying the effect of the activation of GLP-1R on memory protection have not yet been established. The spared nerve injury (SNI) model was established as a kind of neuropathic pain. And novel-object recognition memory (hippocampus-dependent memory) was tested by the novel object recognition test (NORT). The expression levels of GLP-1, GLP-1R, adenosine monophosphate-activated protein kinase (AMPK), p-AMPKThr172, nuclear factor κ B p65 (NF-κB p65), interleukin-1beta (IL-1β), IL-1β p17 (mature IL-1β), tumor necrosis factor-alpha (TNF-α) and the synaptic proteins were tested in the murine hippocampus with memory deficits caused by neuropathic pain. Then, exenatide acetate (Ex-4, a GLP-1R agonist), exendin (9–39) (Ex(9–39), a GLP-1R antagonist) and Compound C dihydrochloride (CC, an AMPK inhibitor) were used to test the effects of the activation of GLP-1R in the mice with neuropathic pain. First, we uncovered that neuropathic pain could inhibit GLP-1/GLP-R axis, disturb inflammatory signaling pathway, increase the expression of IL-1β, IL-1β p17 and TNF-α, downregulate the synaptic proteins (postsynaptic density protein 95 (PSD95) and Arc). Subsequently, we reported that Ex-4 treatment could improve recognition memory impairment, increase the ratio of p-AMPKThr172/AMPK, inhibit the phosphorylation NF-κB p65 and decrease the expression of IL-1β, IL-1β p17 and TNF-α, upregulate the levels of PSD95 and Arc. Moreover, we found that Ex(9–39) and CC treatment could abrogate the memory protection of activation of GLP-1R in mice with neuropathic pain. The results indicated that the activation of GLP-1R could improve recognition memory impairment via regulating AMPK/NF-κB pathway, improving neuroinflammation, reversing the decreased level of synaptic proteins in neuropathic pain mice.



中文翻译:

GLP-1R激活通过调节神经性疼痛小鼠海马AMPK/NF-κB通路改善新物体识别记忆功能障碍

越来越多的证据表明,神经性疼痛常伴有认知障碍,加剧了慢性疼痛患者生活质量的下降。此外,已经表明胰高血糖素样肽 1 受体 (GLP-1R) 的激活改善了多种疾病的记忆缺陷,包括阿尔茨海默病 (AD)、中风。然而,GLP-1R 激活是否可以改善神经性疼痛引起的记忆障碍以及 GLP-1R 激活对记忆保护作用的潜在机制尚未确定。保留神经损伤(SNI)模型被建立为一种神经性疼痛。新物体识别记忆(海马依赖性记忆)通过新物体识别测试(NORT)进行测试。GLP-1、GLP-1R、腺苷一磷酸活化蛋白激酶 (AMPK)、p-AMPKThr172、核因子 κ B p65 (NF-κB p65)、白介素-1β (IL-1β)、IL-1β p17 (成熟 IL-1β)、肿瘤坏死因子- α (TNF-α) 和突触蛋白在由神经性疼痛引起的记忆缺陷的小鼠海马中进行了测试。然后,使用醋酸艾塞那肽(Ex-4,一种 GLP-1R 激动剂)、exendin (9-39)(Ex(9-39),一种 GLP-1R 拮抗剂)和化合物 C 二盐酸盐(CC,一种 AMPK 抑制剂)测试 GLP-1R 激活对神经性疼痛小鼠的影响。首先,我们发现神经性疼痛可抑制 GLP-1/GLP-R 轴,扰乱炎症信号通路,增加 IL-1β、IL-1β p17 和 TNF-α 的表达,下调突触蛋白(突触后密度蛋白 95( PSD95) 和弧)。随后,我们报道 Ex-4 治疗可以改善识别记忆障碍,增加 p-AMPKThr172/AMPK 的比率,抑制磷酸化 NF-κB p65 并降低 IL-1β、IL-1β p17 和 TNF-α 的表达,上调PSD95 和 Arc 的级别。此外,我们发现 Ex(9-39) 和 CC 治疗可以消除神经性疼痛小鼠中 GLP-1R 激活的记忆保护。结果表明,GLP-1R的激活可通过调节AMPK/NF-κB通路改善认知记忆障碍,改善神经炎症,逆转神经性疼痛小鼠突触蛋白水平下降。此外,我们发现 Ex(9-39) 和 CC 治疗可以消除神经性疼痛小鼠中 GLP-1R 激活的记忆保护。结果表明,GLP-1R的激活可通过调节AMPK/NF-κB通路改善认知记忆障碍,改善神经炎症,逆转神经性疼痛小鼠突触蛋白水平下降。此外,我们发现 Ex(9-39) 和 CC 治疗可以消除神经性疼痛小鼠中 GLP-1R 激活的记忆保护。结果表明,GLP-1R的激活可通过调节AMPK/NF-κB通路改善认知记忆障碍,改善神经炎症,逆转神经性疼痛小鼠突触蛋白水平下降。

更新日期:2021-05-24
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