Department of Neurophysiology and Neuropharmacology, Institute of Nautical Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, Jiangsu, 226019, China.
Department of Neurophysiology and Neuropharmacology, Institute of Nautical Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, Jiangsu, 226019, China.
Neuropharmacology. 2019 Mar 1;146:39-49. doi: 10.1016/j.neuropharm.2018.11.025. Epub 2018 Nov 16.
Demyelination in white matter is the end product of numerous pathological processes. This study was designed to evaluate the neuroprotective effect of l-serine and the underlying mechanisms against the demyelinating injury of white matter. A model of focal demyelinating lesions (FDL) was established using the two-point stereotactic injection of 0.25% lysophosphatidylcholine (LPC, 10 μg per point) into the corpus callosum of mice. Mice were then intraperitoneally injected with one of three doses of l-serine (114, 342, or 1026 mg/kg) 2 h after FDL, and then twice daily for the next five days. Behavior tests and histological analysis were assessed for up to twenty-eight days post-FDL induction. Electron microscopy was used for ultrastructural investigation. In vitro, we applied primary co-cultures of microglia and oligodendrocytes for oxygen glucose deprivation (OGD). After establishing FDL, l-serine treatment: 1) improved spatial learning, memory and cognitive ability in mice, and relieved anxiety for 4 weeks post-FDL induction; 2) reduced abnormally dephosphorylated neurofilament proteins, increased myelin basic protein, and preserved anatomic myelinated axons; 3) inhibited microglia activation and reduced the release of inflammatory factors; 4) promoted recruitment and proliferation of oligodendrocyte progenitor cells, and the efficiency of subsequent remyelination on day twenty-eight post-FDL induction. In vitro experiments, showed that l-serine not only directly protected against oligodendrocytes from OGD damage, but also provided an indirect protective effect by regulating microglia. In our study, l-serine offered long-lasting behavioral and oligodendrocyte protection and promoted remyelination. Therefore, l-serine may be an effective clinical treatment aganist white matter injury.
脱髓鞘是许多病理过程的终末产物。本研究旨在评估 l-丝氨酸对脱髓鞘白质损伤的神经保护作用及其潜在机制。通过两点立体定位将 0.25%溶血磷脂酰胆碱（LPC，每点 10μg）注射到小鼠胼胝体中，建立局灶性脱髓鞘病变（FDL）模型。FDL 后 2 小时，小鼠腹腔内注射三种剂量的 l-丝氨酸（114、342 或 1026mg/kg）中的一种，然后连续 5 天每天两次。行为测试和组织学分析评估持续 28 天。电子显微镜用于超微结构研究。体外，我们应用小胶质细胞和少突胶质细胞的原代共培养物进行氧葡萄糖剥夺（OGD）。在建立 FDL 后，l-丝氨酸治疗：1）改善了 FDL 诱导后 4 周内小鼠的空间学习、记忆和认知能力，缓解了焦虑；2）减少了异常去磷酸化的神经丝蛋白，增加了髓鞘碱性蛋白，保留了有髓轴突的解剖结构；3）抑制了小胶质细胞的激活，减少了炎症因子的释放；4）促进了少突胶质细胞前体细胞的募集和增殖，并提高了 FDL 诱导后第 28 天的髓鞘再生效率。体外实验表明，l-丝氨酸不仅直接保护少突胶质细胞免受 OGD 损伤，还通过调节小胶质细胞发挥间接保护作用。在本研究中，l-丝氨酸提供了持久的行为和少突胶质细胞保护作用，并促进了髓鞘再生。因此，l-丝氨酸可能是一种有效的治疗白质损伤的临床药物。
