In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany.
In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany; Percuros B.V., Enschede, The Netherlands.
Biomaterials. 2016 Jun;91:151-165. doi: 10.1016/j.biomaterials.2016.03.025. Epub 2016 Mar 19.
microRNA-124 (miR-124), the most abundant miRNA of the CNS, was recently shown to modulate the polarization of activated microglia and infiltrating macrophages towards the anti-inflammatory M2 phenotype and protect neurons in various ways after brain disease. In ischemic stroke, microglia and macrophages of a detrimental and persistent pro-inflammatory M1 phenotype have been shown to aggravate the secondary injury. Thus, shifting the polarization of microglia/macrophages into the beneficial, anti-inflammatory M2-like phenotype is considered neuroprotective after stroke onset. Here, we have induced 30 min transient occlusion of the right middle cerebral artery (MCAO) in 34 male, C57BL/6 mice. Lesion development was monitored with T2-weighted MRI. Liposomated miR-124 was injected in 11 animals at 48 h and in 5 animals at 10 days after MCAO. Arg-1, a marker for M2 phenotype, was co-stained with Iba-1, NeuN or GFAP. The distribution of astrocytes, neurons and microglia/macrophages and their expression of Arg-1 were quantified. Early miR-124 injection resulted in a significantly increased neuronal survival and a significantly increased number of M2-like polarized microglia/macrophages. Moreover, the lesion core, delineated by reactive astrocytes, was significantly reduced over time upon early miR-124 injection. These neuroprotective and anti-inflammatory effects of the early miR-124 treatment were pronounced during the first week with Arg-1. Number of Arg-1+ microglia/macrophages correlated with neuronal protection and with functional improvement during the first week. Thus, our present results demonstrate that miR-124 may serve as a novel therapeutic strategy for neuroprotection and functional recovery upon stroke onset.
微小 RNA-124（miR-124）是中枢神经系统中含量最丰富的 miRNA，最近研究表明它可以调节激活的小胶质细胞和浸润的巨噬细胞向抗炎 M2 表型极化，并以多种方式保护神经元免受各种脑部疾病的影响。在缺血性中风中，已证明具有有害和持续促炎 M1 表型的小胶质细胞和巨噬细胞会加重继发性损伤。因此，在中风发作后，将小胶质细胞/巨噬细胞的极化转向有益的抗炎 M2 样表型被认为具有神经保护作用。在这里，我们在 34 只雄性 C57BL/6 小鼠中诱导了右侧大脑中动脉（MCAO） 30 分钟的短暂闭塞。通过 T2 加权 MRI 监测损伤发展。在 MCAO 后 48 小时和 10 天，在 11 只动物中注射了脂质体包裹的 miR-124，在 5 只动物中注射了 miR-124。用 Iba-1、NeuN 或 GFAP 共染色 Arg-1，作为 M2 表型的标志物。定量分析星形胶质细胞、神经元和小胶质细胞/巨噬细胞的分布及其 Arg-1 的表达。早期 miR-124 注射可显著增加神经元存活率，并显著增加 M2 样极化的小胶质细胞/巨噬细胞数量。此外，早期 miR-124 注射可随时间推移显著减少由反应性星形胶质细胞界定的损伤核心。早期 miR-124 治疗的这种神经保护和抗炎作用在 Arg-1 的第一周内表现明显。Arg-1+小胶质细胞/巨噬细胞的数量与神经元保护和第一周的功能改善相关。因此，我们目前的结果表明，miR-124 可能成为中风发作后神经保护和功能恢复的新治疗策略。
