Modulation of Microglial Activation by Adenosine A2a Receptor in Animal Models of Perinatal Brain Injury.
Modulation of Microglial Activation by Adenosine A2a Receptor in Animal Models of Perinatal Brain Injury.
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DOI：
10.3389/fneur.2018.00605
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发表时间：
2018
影响因子：
3.4
通讯作者：
Baud O
中科院分区：
文献类型：
--
作者：
Colella M;Zinni M;Pansiot J;Cassanello M;Mairesse J;Ramenghi L;Baud O
神经炎症在围产期脑损伤的发病机制中起关键作用。咖啡因是腺苷受体（AR）的非特异性拮抗剂，被广泛用于治疗早产儿呼吸暂停，并与早产儿脑瘫发病率的降低有关。解释其神经保护作用的机制尚未阐明。本研究的目的是表征腺苷和AR在两种新生大鼠神经炎症模型中的表达，并确定A2 aR阻断对通过炎性细胞因子基因表达评估的小胶质细胞活化的影响。我们使用了两种小胶质细胞激活的大鼠模型：妊娠期低蛋白饮食（LPD）模型，与慢性脑损伤，和出生后鹅膏蕈氨酸脑内注射，负责急性兴奋性毒性损伤。腺苷血液水平已通过串联质谱法测量。使用qPCR和免疫组织化学评估体内AR的表达。已在暴露于A2 aR激动剂CGS-21680或拮抗剂SCH-58261的原代小胶质细胞培养物中体外复制了体内模型。已经评估了这些处理对通过RT-qPCR测量的M1/M2细胞因子表达的影响。妊娠期间LPD与出生后第1天和第4天幼崽中较高的腺苷水平相关。与对照组相比，LPD动物的皮质和磁分选小胶质细胞中A2 aR mRNA表达显著增加。负责脑腺苷细胞外产生的CD 73表达在LPD皮质和分选的小胶质细胞中显著增加。此外，鹅膏蕈氨酸治疗的动物中的CD 73蛋白水平增加。体外实验证实，暴露于鹅膏蕈氨酸的LPD或对照小胶质细胞在蛋白质和分子水平上显示A2 aR和M1标志物（IL-1β、IL-6、iNOS、TNFα）的表达增加。SCH-58261显著降低了这种促炎特征，可降低LPD和鹅膏蕈氨酸暴露细胞中的M1标志物，对对照细胞无影响。在相同的实验条件下，观察到部分增加的M1细胞因子响应A2 aR激动剂CGS-21680。这些结果支持参与腺苷，特别是其受体A2 aR在两种不同的动物模型的神经炎症的小胶质细胞的调节。
Neuroinflammation has a key role in the pathogenesis of perinatal brain injury. Caffeine, a nonspecific antagonist of adenosine receptors (ARs), is widely used to treat apnea of prematurity and has been linked to a decrease in the incidence of cerebral palsy in premature infants. The mechanisms explaining its neuroprotective effect have not yet been elucidated. The objective of this study was to characterize the expression of adenosine and ARs in two neonatal rat models of neuroinflammation and to determine the effect of A2aR blockade on microglial activation assessed through inflammatory cytokine gene expression. We have used two rat models of microglial activation: the gestational low protein diet (LPD) model, associated with chronic brain injury, and postnatal ibotenate intracerebral injections, responsible for acute excitotoxicity injury. Adenosine blood levels have been measured by Tandem Mass Spectrometry. The expression of ARs in vivo was assessed using qPCR and immunohistochemistry. In vivo models have been replicated in vitro on primary microglial cell cultures exposed to A2aR agonist CGS-21680 or antagonist SCH-58261. The effects of these treatments have been assessed on the M1/M2 cytokine expressions measured by RT-qPCR. LPD during pregnancy was associated with higher adenosine levels in pups at postnatal day 1 and 4. A2aR mRNA expression was significantly increased in both cortex and magnetically sorted microglial cells from LPD animals compared to controls. CD73 expression, responsible for extracellular production of brain adenosine, was significantly increased in LPD cortex and sorted microglia cells. Moreover, CD73 protein level was increased in ibotenate treated animals. In vitro experiments confirmed that LPD or control microglial cells exposed to ibotenate display an increased expression, at both protein and molecular levels, of A2aR and M1 markers (IL-1β, IL-6, iNOS, TNFα). This pro-inflammatory profile was significantly reduced by SCH-58261, which reduces M1 markers in both LPD and ibotenate-exposed cells, with no effect on control cells. In the same experimental conditions, a partial increased of M1 cytokines was observed in response to A2aR agonist CGS-21680. These results support the involvement of adenosine and particularly of its receptor A2aR in the regulation of microglia in two different animal models of neuroinflammation.
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影响因子：
5.3
作者：
Augusto, Elisabete;Matos, Marco;Chen, Jiang-Fan
通讯作者：
Chen, Jiang-Fan
影响因子：
5.3
作者：
Li, Wei;Dai, Shuangshuang;Zhou, Yuanguo
通讯作者：
Zhou, Yuanguo
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.8
作者：
Kuban KC;O'Shea TM;Allred EN;Fichorova RN;Heeren T;Paneth N;Hirtz D;Dammann O;Leviton A;ELGAN Study Investigators
通讯作者：
ELGAN Study Investigators
DOI：
10.1056/nejmra1205750
发表时间：
2012-12-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eltzschig HK;Sitkovsky MV;Robson SC
通讯作者：
Robson SC