Galantamine improves cognition, hippocampal inflammation, and synaptic plasticity impairments induced by lipopolysaccharide in mice.
Galantamine improves cognition, hippocampal inflammation, and synaptic plasticity impairments induced by lipopolysaccharide in mice.
复制标题
加兰他敏改善小鼠认知、海马炎症和脂多糖引起的突触可塑性损伤
DOI：
10.1186/s12974-018-1141-5
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发表时间：
2018-04-18
影响因子：
9.3
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Liu Y;Zhang Y;Zheng X;Fang T;Yang X;Luo X;Guo A;Newell KA;Huang XF;Yu Y
神经炎症在阿尔茨海默病等神经退行性疾病的发生和发展中起着重要作用。脂多糖（LPS，内毒素）水平在阿尔茨海默病患者的大脑中较高，并且与神经炎症和认知下降相关，而神经胆碱能信号传导控制炎症。本研究旨在研究加兰他敏（一种临床批准的胆碱能药物）在减轻LPS诱导的神经炎症和认知能力下降方面的疗效及其相关机制。在LPS暴露（脑室内注射）之前，用加兰他敏（4 mg/kg，腹膜内注射）处理小鼠14天。进行认知测试，包括Morris水迷宫和避暗测试。通过定量RT-PCR检测海马中小胶质细胞标志物（CD 11b）、星形胶质细胞标志物（GFAP）和促炎细胞因子（IL-1β、IL-6和TNF-α）的mRNA表达。免疫印迹法检测海马组织中炎症信号分子核因子-κ B（NF-κB p65）和突触相关蛋白（突触素SYN和突触后密度蛋白95 PSD-95）的表达。此外，检测LPS和加兰他敏对小胶质细胞和海马神经元中NF-κB p65水平的响应。加兰他敏治疗可预防LPS诱导的空间学习和记忆缺陷以及被动回避反应的记忆获得。加兰他敏降低LPS暴露小鼠海马区小胶质细胞和星形胶质细胞标志物（CD 11 B和GFAP）、促炎细胞因子（IL-1β、IL-6和TNF-α）和NF-κB p65的表达。此外，加兰他敏改善LPS诱导的海马突触相关蛋白（SYN和PSD-95）的丢失。在体外研究中，LPS增加了小胶质细胞（BV-2细胞）中NF-κB p65的水平; LPS刺激的小胶质细胞（Mi-sup）的上清液（但不是LPS）降低了海马神经元细胞（HT-22细胞）的活力，并增加了HT-22细胞中NF-κB p65的水平以及促炎细胞因子（IL-1β，IL-6）的表达。重要的是，加兰他敏不仅在BV-2小胶质细胞系中，而且在HT-22海马神经元细胞系中减少炎症反应。这些发现表明加兰他敏可能是一种有前途的治疗方法，可以改善神经退行性疾病中内毒素诱导的认知下降和神经炎症。
Neuroinflammation plays an important role in the onset and progression of neurodegenerative diseases such as Alzheimer’s disease. Lipopolysaccharide (LPS, endotoxin) levels are higher in the brains of Alzheimer’s disease patients and are associated with neuroinflammation and cognitive decline, while neural cholinergic signaling controls inflammation. This study aimed to examine the efficacy of galantamine, a clinically approved cholinergic agent, in alleviating LPS-induced neuroinflammation and cognitive decline as well as the associated mechanism. Mice were treated with galantamine (4 mg/kg, intraperitoneal injection) for 14 days prior to LPS exposure (intracerebroventricular injection). Cognitive tests were performed, including the Morris water maze and step-through tests. mRNA expression of the microglial marker (CD11b), astrocytic marker (GFAP), and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) were examined in the hippocampus by quantitative RT-PCR. The inflammatory signaling molecule, nuclear factor-kappa B (NF-κB p65), and synapse-associated proteins (synaptophysin, SYN, and postsynaptic density protein 95, PSD-95) were examined in the hippocampus by western blotting. Furthermore, NF-κB p65 levels in microglial cells and hippocampal neurons were examined in response to LPS and galantamine. Galantamine treatment prevented LPS-induced deficits in spatial learning and memory as well as memory acquisition of the passive avoidance response. Galantamine decreased the expression of microglia and astrocyte markers (CD11b and GFAP), pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and NF-κB p65 in the hippocampus of LPS-exposed mice. Furthermore, galantamine ameliorated LPS-induced loss of synapse-associated proteins (SYN and PSD-95) in the hippocampus. In the in vitro study, LPS increased NF-κB p65 levels in microglia (BV-2 cells); the supernatant of LPS-stimulated microglia (Mi-sup), but not LPS, decreased the viability of hippocampal neuronal cells (HT-22 cells) and increased NF-κB p65 levels as well as expression of pro-inflammatory cytokines (IL-1β, IL-6) in HT-22 cells. Importantly, galantamine reduced the inflammatory response not only in the BV-2 microglia cell line, but also in the HT-22 hippocampal neuronal cell line. These findings indicate that galantamine could be a promising treatment to improve endotoxin-induced cognitive decline and neuroinflammation in neurodegenerative diseases.
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影响因子：
29
作者：
Baker RG;Hayden MS;Ghosh S
通讯作者：
Ghosh S
DOI：
10.1016/j.bbadis.2015.08.016
发表时间：
2015-11
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Cisternas P;Salazar P;Serrano FG;Montecinos-Oliva C;Arredondo SB;Varela-Nallar L;Barja S;Vio CP;Gomez-Pinilla F;Inestrosa NC
通讯作者：
Inestrosa NC
DOI：
10.1016/j.ijdevneu.2014.06.011
发表时间：
2014-10-01
影响因子：
1.8
作者：
Furukawa, Seishi;Yang, Li;Sameshima, Hiroshi
通讯作者：
Sameshima, Hiroshi
影响因子：
3.6
作者：
Hu, Yan-Dan;Pang, Wei;Jiang, Yu-Gang
通讯作者：
Jiang, Yu-Gang
影响因子：
3.3
作者：
Hornick, A.;Lieb, A.;Vo, N. P.;Rollinger, J. M.;Stuppner, H.;Prast, H.
通讯作者：
Prast, H.