Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice
Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice
复制标题
DOI：
10.1016/j.expneurol.2010.12.010
复制
发表时间：
2011-03-01
影响因子：
5.3
通讯作者：
Kriz, Jasna
中科院分区：
文献类型：
--
作者：
Keller, A. Florence;Gravel, Mathieu;Kriz, Jasna
一些报告已经证明，米诺环素（一种具有抗炎特性的抗微生物药物）对小胶质细胞活化的减弱延缓了ALS小鼠模型中的疾病进展。然而，在最近的临床试验中获得的负面结果提出了一些关于炎症反应和神经胶质细胞作为ALS治疗靶点的作用的问题。为了研究这一争议，我们利用小鼠模型对ALS中的神经炎症反应进行实时成像（GFAP-luc/SOD 1（G93 A）报告小鼠），并在真实的时间内分析在疾病的不同阶段开始的米诺环素治疗的效果。令我们惊讶的是，与二甲胺四环素在术前给药时赋予的神经保护不同，在疾病发作后开始的二甲胺四环素治疗显著改变了神经胶质反应并加剧了神经炎症。进一步的分析显示，晚期米诺环素治疗与终末期GFAP-生物光子信号的显著诱导、连接蛋白43（星形胶质细胞间隙连接的主要蛋白）和小胶质细胞活化的标志物（如Iba 1和CD 68）的表达水平相关。我们的研究结果表明，当在疾病后期给药时，一旦小胶质细胞呈慢性反应性，米诺环素可能不具有抗炎特性，与预期相反，可能会改变星形胶质细胞的反应性并增加小胶质细胞增生。最后，我们的研究结果进一步表明，在晚期ALS中，激活的小胶质细胞和星形胶质细胞之间存在密切的相互作用/交流。皇冠版权所有（C）2010由爱思唯尔公司出版。All rights reserved.
Several reports have demonstrated that attenuation of microglial activation by minocycline, an antimicrobial drug with anti-inflammatory properties, delays disease progression in a mouse model of ALS. However, the negative results obtained in recent clinical trials raised some questions regarding the role of inflammatory response and glial cells as a therapeutic target in ALS. To investigate this controversy we took advantage of a mouse model for live imaging of neuroinflammatory responses in ALS (GFAP-luc/SOD1(G93A) reporter mouse) and analyzed in real time the effects of minocycline treatment initiated at different stages of the disease. To our surprise, unlike neuroprotection that is conferred when minocycline is administered pre-symptomatically, treatment with minocycline initiated after the disease onset significantly altered glial responses and exaggerated neuroinflammation. Further analysis revealed that the late minocycline treatment was associated with significant induction of the end-stage GFAP-biophotonic signals, expression levels of connexin 43, a major protein of astrocytic gap junction and markers of microglial activation, such as Iba1 and CD68. The results of our study suggest that when administered at later stages of disease, once microglial cells are chronically reactive, minocycline may not have anti-inflammatory properties, and contrary to expectations, may alter astrocyte reactivity and increase microgliosis. Finally, our results further suggest the existence of close interactions/communication between activated microglia and astrocytes in late stage ALS. Crown Copyright (C) 2010 Published by Elsevier Inc. All rights reserved.