Li W-J, Mao F-X, Chen H-J, Qian L-H, Buzby J S
Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai 200092, China.
Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Jianshe East Road No. 1, Zhengzhou 450052, China.
Neuroscience. 2015 Jan 22;284:444-458. doi: 10.1016/j.neuroscience.2014.10.012. Epub 2014 Oct 16.
Periventricular leukomalacia (PVL) is one of the foremost neurological conditions leading to long-term abnormalities in premature infants. Since it is difficult to prevent initiation of this damage in utero, promoting the innate regenerative potential of the brain after birth may provide a more feasible, prospective therapy for PVL. Treatment with UDP-glucose (UDPG), an endogenous agonist of G protein-coupled receptor 17 (GPR17) that may enhance endogenous self-repair potentiality, glial cell line-derived neurotrophic factor (GDNF), a neurotrophic factor associated with the growth and survival of nerve cells, and memantine, a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors that block ischemia-induced glutamate signal transduction, has been reported to achieve functional, neurological improvement in neonatal rats with PVL. The aim of the present study was to further explore whether UDPG, GDNF and/or memantine could promote corresponding self-repair of the subventricular zone (SVZ) and white matter (WM) in neonatal rats with ischemia-induced PVL. SVZ or WM tissue samples and cultured glial progenitor cells derived from a 5 day-old neonatal rat model of PVL were utilized for studying response to UDPG, GDNF and memantine in vivo and in vitro, respectively. Labeling with 5'-bromo-2'-deoxyuridine and immunofluorescent cell lineage markers after hypoxia-ischemia or oxygen-glucose deprivation (OGD) revealed that UDPG, GDNF and memantine each significantly increased glial progenitor cells and preoligodendrocytes (preOLs), as well as more differentiated immature and mature oligodendrocyte (OL), in both the SVZ and WM in vivo or in vitro. SVZ and WM glial cell apoptosis was also significantly reduced by UDPG, GDNF or memantine, both in vivo and in vitro. These results indicated that UDPG, GDNF or memantine may promote endogenous self-repair by stimulating proliferation of glial progenitor cells derived from both the SVZ and WM, activating their differentiation into more mature OLs, and raising the survival rate of these newly generated glial cells in neonatal rats with ischemic PVL.
脑室周围白质软化（PVL）是导致早产儿长期异常的主要神经疾病之一。由于在子宫内难以预防这种损伤的发生，促进出生后大脑的固有再生潜能可能为PVL提供一种更可行的前瞻性治疗方法。据报道，用UDP-葡萄糖（UDPG）（一种可能增强内源性自我修复潜能的G蛋白偶联受体17（GPR17）的内源性激动剂）、胶质细胞源性神经营养因子（GDNF）（一种与神经细胞生长和存活相关的神经营养因子）和美金刚（一种N-甲基-D-天冬氨酸（NMDA）受体的非竞争性拮抗剂，可阻断缺血诱导的谷氨酸信号转导）进行治疗，可使患有PVL的新生大鼠在功能和神经方面得到改善。本研究的目的是进一步探讨UDPG、GDNF和/或美金刚是否能促进缺血诱导的PVL新生大鼠脑室下区（SVZ）和白质（WM）的相应自我修复。分别利用来自5日龄PVL新生大鼠模型的SVZ或WM组织样本以及培养的胶质祖细胞，在体内和体外研究它们对UDPG、GDNF和美金刚的反应。在缺氧缺血或氧糖剥夺（OGD）后用5'-溴-2'-脱氧尿苷标记和免疫荧光细胞谱系标记物显示，UDPG、GDNF和美金刚在体内或体外均能显著增加SVZ和WM中的胶质祖细胞和前少突胶质细胞（preOLs），以及更多分化的未成熟和成熟少突胶质细胞（OL）。UDPG、GDNF或美金刚在体内和体外也显著降低了SVZ和WM胶质细胞的凋亡。这些结果表明，UDPG、GDNF或美金刚可能通过刺激源自SVZ和WM的胶质祖细胞增殖，激活它们分化为更成熟的OL，并提高缺血性PVL新生大鼠这些新生成的胶质细胞的存活率，从而促进内源性自我修复。
