Dimethyl fumarate attenuates reactive microglia and long-term memory deficits following systemic immune challenge.
Dimethyl fumarate attenuates reactive microglia and long-term memory deficits following systemic immune challenge.
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DOI：
10.1186/s12974-018-1125-5
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发表时间：
2018-03-29
影响因子：
9.3
通讯作者：
Yu IC
中科院分区：
文献类型：
--
作者：
Paraiso HC;Kuo PC;Curfman ET;Moon HJ;Sweazey RD;Yen JH;Chang FL;Yu IC
全身性炎症与认知能力下降和阿尔茨海默病风险增加有关。全身炎症期间激活的小胶质细胞（MG）可导致过度的神经炎症反应并引发进行性神经退行性变。富马酸二甲酯（DMF）是FDA批准的多发性硬化症治疗药物。DMF的免疫调节和抗氧化特性促使我们研究DMF是否具有治疗与全身炎症相关的认知障碍的转化潜力。在不存在或存在DMF的情况下，用脂多糖（LPS）刺激原代鼠MG培养物。使用从核因子（红细胞衍生2）样2缺陷型（Nrf 2 −/−）小鼠培养的MG来检查DMF的作用机制。由LPS引发的MG产生的条件培养基用于处理海马神经元培养物。成年C57 BL/6和Nrf 2 −/−小鼠接受外周LPS攻击。检查急性神经炎症、长期记忆功能和反应性星形胶质细胞增生，以评估DMF的治疗效果。DMF抑制LPS诱导的MG炎症活化。DMF通过Nrf 2依赖性和Nrf 2非依赖性机制抑制MG中NF-κB活性。DMF处理降低MG介导的对神经元的毒性。DMF抑制外周LPS激发后小鼠脑源性炎症细胞因子。DMF对Nrf 2 −/−小鼠神经炎症的抑制作用减弱。重要的是，DMF治疗缓解了长期记忆缺陷和持续的反应性星形胶质细胞增生诱导的外周脂多糖挑战。DMF可能减轻与神经炎症相关的神经毒性星形胶质细胞。DMF处理可能保护神经元免受与全身炎症相关的反应性MG和星形胶质细胞产生的毒性微环境的影响。本文的在线版本（10.1186/s12974-018-1125-5）包含补充材料，可供授权用户使用。
Systemic inflammation is associated with increased cognitive decline and risk for Alzheimer’s disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is a FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation. Primary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2−/−) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2−/− mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF. DMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2−/− mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation. DMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation. The online version of this article (10.1186/s12974-018-1125-5) contains supplementary material, which is available to authorized users.
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影响因子：
--
作者：
Goldmann T;Prinz M
通讯作者：
Prinz M
影响因子：
168.9
作者：
Inouye, Sharon K.;Westendorp, Rudi G. J.;Saczynski, Jane S.
通讯作者：
Saczynski, Jane S.
影响因子：
3.5
作者：
Branca, Caterina;Ferreira, Eric;Oddo, Salvatore
通讯作者：
Oddo, Salvatore
影响因子：
9.3
作者：
Krstic D;Madhusudan A;Doehner J;Vogel P;Notter T;Imhof C;Manalastas A;Hilfiker M;Pfister S;Schwerdel C;Riether C;Meyer U;Knuesel I
通讯作者：
Knuesel I
富马酸二甲酯通过改变 M1/M2 巨噬细胞的平衡，通过核因子红细胞衍生 2 相关因子 2/hemoxygenase-1 途径减轻实验性自身免疫性神经炎。
影响因子：
9.3
作者：
Han R;Xiao J;Zhai H;Hao J
通讯作者：
Hao J