4R-cembranoid suppresses glial cells inflammatory phenotypes and prevents hippocampal neuronal loss in LPS-treated mice

IF 2.9 3区 医学 Q2 NEUROSCIENCES
Luis A. Rojas-Colón, John B. Redell, Pramod K. Dash, Pedro E. Vegas, Wanda Vélez-Torres
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Abstract

Chronic neuroinflammation has been implicated in neurodegenerative disease pathogenesis. A key feature of neuroinflammation is neuronal loss and glial activation, including microglia and astrocytes. 4R-cembranoid (4R) is a natural compound that inhibits hippocampal pro-inflammatory cytokines and increases memory function in mice. We used the lipopolysaccharide (LPS) injection model to study the effect of 4R on neuronal density and microglia and astrocyte activation. C57BL/6J wild-type mice were injected with LPS (5 mg/kg) and 2 h later received either 4R (6 mg/kg) or vehicle. Mice were sacrificed after 72 h for analysis of brain pathology. Confocal images of brain sections immunostained for microglial, astrocyte, and neuronal markers were used to quantify cellular hippocampal phenotypes and neurons. Hippocampal lysates were used to measure the expression levels of neuronal nuclear protein (NeuN), inducible nitrous oxide synthase (iNOS), arginase-1, thrombospondin-1 (THBS1), glial cell-derived neurotrophic factor (GDNF), and orosomucoid-2 (ORM2) by western blot. iNOS and arginase-1 are widely used protein markers of pro- and anti-inflammatory microglia, respectively. GDNF promotes neuronal survival, and ORM2 and THBS1 are astrocytic proteins that regulate synaptic plasticity and inhibit microglial activation. 4R administration significantly reduced neuronal loss and the number of pro-inflammatory microglia 72 h after LPS injection. It also decreased the expression of the pro-inflammatory protein iNOS while increasing arginase-1 expression, supporting its anti-inflammatory role. The protein expression of THBS1, GDNF, and ORM2 was increased by 4R. Our data show that 4R preserves the integrity of hippocampal neurons against LPS-induced neuroinflammation in mice.

Abstract Image

4R-cembranoid 可抑制神经胶质细胞的炎症表型,防止经 LPS 处理的小鼠海马神经元丧失
慢性神经炎症与神经退行性疾病的发病机制有关。神经炎症的一个主要特征是神经元丧失和神经胶质细胞(包括小胶质细胞和星形胶质细胞)激活。4R-cembranoid(4R)是一种天然化合物,可抑制海马促炎细胞因子并增强小鼠的记忆功能。我们使用脂多糖(LPS)注射模型来研究 4R 对神经元密度以及小胶质细胞和星形胶质细胞活化的影响。给 C57BL/6J 野生型小鼠注射 LPS(5 毫克/千克),2 小时后再注射 4R(6 毫克/千克)或药物。小鼠在 72 小时后被处死,以进行脑病理学分析。免疫染色小胶质细胞、星形胶质细胞和神经元标记物的脑切片共聚焦图像用于量化细胞海马表型和神经元。海马裂解液被用来通过 Western 印迹法测定神经元核蛋白(NeuN)、诱导型一氧化氮合酶(iNOS)、精氨酸酶-1、血栓软蛋白-1(THBS1)、胶质细胞源性神经营养因子(GDNF)和类粘滞蛋白-2(ORM2)的表达水平。GDNF能促进神经元存活,ORM2和THBS1是星形胶质细胞蛋白,能调节突触可塑性并抑制小胶质细胞活化。注射 LPS 72 小时后,服用 4R 能明显减少神经元损失和促炎性小胶质细胞的数量。它还降低了促炎蛋白 iNOS 的表达,同时增加了精氨酸酶-1 的表达,支持其抗炎作用。4R 增加了 THBS1、GDNF 和 ORM2 的蛋白表达。我们的数据表明,4R 能保护小鼠海马神经元的完整性,防止 LPS 引起的神经炎症。
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来源期刊
Journal of Neuroscience Research
Journal of Neuroscience Research 医学-神经科学
CiteScore
9.50
自引率
2.40%
发文量
145
审稿时长
1 months
期刊介绍: The Journal of Neuroscience Research (JNR) publishes novel research results that will advance our understanding of the development, function and pathophysiology of the nervous system, using molecular, cellular, systems, and translational approaches. JNR covers both basic research and clinical aspects of neurology, neuropathology, psychiatry or psychology. The journal focuses on uncovering the intricacies of brain structure and function. Research published in JNR covers all species from invertebrates to humans, and the reports inform the readers about the function and organization of the nervous system, with emphasis on how disease modifies the function and organization.
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