Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells.
Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells.
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DOI：
10.1186/s12974-015-0305-9
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发表时间：
2015-04-28
影响因子：
9.3
通讯作者：
Rinne JO
中科院分区：
文献类型：
--
作者：
Pihlaja R;Takkinen J;Eskola O;Vasara J;López-Picón FR;Haaparanta-Solin M;Rinne JO
最近，单酰基甘油脂酶（MAGL）的作用，同时前列腺素合成和内源性大麻素受体激活在中枢神经系统中的主要调节剂被证明。为了扩展该领域先前发表的研究，我们观察了MAGL抑制剂JZL 184在阿尔茨海默病小鼠模型APdE 9中早期促炎反应和β-淀粉样蛋白（Aβ）形成过程中的作用。我们还研究了其在促炎剂诱导的成年小鼠星形胶质细胞和小胶质细胞中的作用。转基因APdE 9小鼠（5月龄）每天用JZL 184（40 mg/kg）或溶媒治疗1个月。与溶剂处理的小鼠相比，靶向放射性配体[18 F]GE-180的神经炎症相关的小胶质细胞特异性转运蛋白（TSPO）的体内结合在多个脑区中轻微降低，但在统计学上不显著。JZL 184处理诱导海马（P < 0.01）和颞顶叶（P < 0.05）皮质中炎症诱导的Iba 1免疫反应性小胶质细胞的表达水平显著降低。JZL 184还可显著降低颞叶（P < 0.001）和顶叶（P < 0.01）皮质的总Aβ负荷，并在一定程度上降低海马的总Aβ负荷。用JZL 184预处理的成人小胶质细胞和星形胶质细胞培养物，然后暴露于神经炎症诱导剂脂多糖（LPS）、干扰素-γ（IFN-γ）和Aβ42，与未经JZL 184处理的细胞相比，其促炎反应显著降低。JZL 184可降低APdE 9小鼠模型中小胶质细胞的促炎反应，并减少总Aβ负荷及其前体。它还减少了从成年小鼠分离的小胶质细胞和星形胶质细胞的促炎反应。
Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer’s disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice. Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [18 F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment. JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.
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影响因子：
2.7
作者：
Wadsworth, Harry;Jones, Paul A.;Trigg, William
通讯作者：
Trigg, William
DOI：
10.1083/jcb.200705042
发表时间：
2007-08-27
期刊：
The Journal of cell biology
影响因子：
--
作者：
He P;Zhong Z;Lindholm K;Berning L;Lee W;Lemere C;Staufenbiel M;Li R;Shen Y
通讯作者：
Shen Y
影响因子：
8.8
作者：
Piro JR;Benjamin DI;Duerr JM;Pi Y;Gonzales C;Wood KM;Schwartz JW;Nomura DK;Samad TA
通讯作者：
Samad TA
影响因子：
5.4
作者：
Wyss-Coray, Tony;Rogers, Joseph
通讯作者：
Rogers, Joseph
影响因子：
3
作者：
Moussaud, Simon;Draheim, Henning Joerg
通讯作者：
Draheim, Henning Joerg