Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Department of Radiology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Brain Behav Immun. 2014 Aug;40:143-54. doi: 10.1016/j.bbi.2014.03.013. Epub 2014 Apr 2.
We previously reported that bone morphogenetic proteins (BMPs) and their endogenous antagonist noggin are expressed in the brain weeks after an ischemic insult. Here, to define their roles in ischemic brain tissue repair and remodeling, we infused recombinant BMP7 or noggin into the ipsilateral ventricle of mice for 2weeks starting 2weeks after transient middle cerebral artery occlusion (MCAO). Four weeks after MCAO, we measured ischemic brain volume, functional recovery, and molecules related to neurogenesis and angiogenesis such as synaptophysin, GAP-43, and VEGF. Noggin-treated mice but not BMP7-treated mice showed preserved ipsilateral brain volume and reduced neurological deficits compared with artificial cerebrospinal fluids (aCSF)-treated mice. Noggin treatment also decreased glial scar thickness, increased levels of GAP-43 and VEGF protein, and increased the number of Iba1-positive activated microglia in the ipsilateral brain. Furthermore, noggin treatment decreased M1 markers (IL-1β, TNF-α, IL-12, CCL2 and CD86) and increased M2 markers (IL-1ra, IL-10, arginase 1, CD206 and Ym1) of activated microglia, suggesting a shift from M1 to M2 phenotypes. These results suggest that noggin improves functional recovery from ischemic stroke and enhances alternatively activated microglia, thereby promoting tissue repair and remodeling.
我们之前报道过，骨形态发生蛋白（BMPs）及其内源性拮抗剂 noggin 在缺血性损伤后数周内在大脑中表达。在这里，为了确定它们在缺血性脑组织修复和重塑中的作用，我们在短暂性大脑中动脉闭塞（MCAO）后 2 周开始向小鼠对侧侧脑室输注重组 BMP7 或 noggin，持续 2 周。MCAO 后 4 周，我们测量了缺血性脑体积、功能恢复以及与神经发生和血管生成相关的分子，如突触素、GAP-43 和 VEGF。与人工脑脊液（aCSF）处理的小鼠相比，noggin 处理的小鼠但不是 BMP7 处理的小鼠显示出保留的同侧脑体积和减少的神经功能缺损。noggin 处理还降低了神经胶质瘢痕的厚度，增加了 GAP-43 和 VEGF 蛋白的水平，并增加了同侧大脑中 Iba1 阳性激活小胶质细胞的数量。此外，noggin 处理降低了激活小胶质细胞的 M1 标志物（IL-1β、TNF-α、IL-12、CCL2 和 CD86），增加了 M2 标志物（IL-1ra、IL-10、精氨酸酶 1、CD206 和 Ym1），表明从 M1 向 M2 表型转变。这些结果表明，noggin 可改善缺血性中风后的功能恢复，并增强交替激活的小胶质细胞，从而促进组织修复和重塑。
