Feng Yiwei, Guo Min, Zhao Hongchen, Han Sida, Hao Yining, Yuan Yiwen, Shen Weiwei, Sun Jian, Dong Qiang, Cui Mei
Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Fudan University, Shanghai, China.
Front Aging Neurosci. 2021 Mar 8;13:632374. doi: 10.3389/fnagi.2021.632374. eCollection 2021.
White matter lesions (WMLs) are a type of cerebrovascular disorder accompanied by demyelination and cognitive decline. Dl-3-n-butylphthalide (D1-NBP) is a neuroprotective drug used for the treatment of ischemic cerebrovascular diseases, although the function of DI-NBP on WML is still not clear. This study aims to investigate whether DI-NBP affects cognitive function and ameliorates demyelination in a model of WML. The bilateral carotid artery stenosis (BCAS) mouse model and brain slice cultures with low glucose and low oxygen (LGLO) treatment were adopted. The Dl-NBP was administered intragastrically for 28 days after BCAS or added at a dose of 50 μm for 48 h after LGLO. Spatial learning and memory were evaluated by an eight-arm radial maze. Demyelination was detected using a TEM. Mitochondrial dynamics were assessed by time-lapse imaging in the cultured brain slices. The function of the synapse was evaluated by the patch clamp technique. In BCAS mice, obvious demyelination and cognitive decline were observed, while both were significantly relieved by a high-dose D1-NBP treatment (100 mg/kg). Along with demyelination, mitochondrial accumulation in the axons was significantly increased in the BCAS mice model, but with the treatment of a high-dose D1-NBP, mitochondrial accumulation was mitigated, and the anterograde/retrograde transport of mitochondria was increased. Following the improved anterograde/retrograde transport of mitochondria, the synapse activity was significantly upregulated while the reactive oxygen species (ROS) generation was remarkably decreased in the cultured brain slices. In addition, we identified syntaphilin (SNPH) as the downstream target of D1-NBP. The overexpression of SNPH mediated the effects of D1-NBP in mitigating axonal mitochondrial accumulation. In conclusion, the D1-NBP treatment significantly relieved demyelination and improved spatial learning and memory in the WML model by promoting mitochondrial dynamics. These neuroprotective effects of D1-NBP were mediated by inhibiting the mitochondrial arching protein, SNPH, which provided a potential therapeutic target for WML.
白质病变（WMLs）是一种伴有脱髓鞘和认知功能衰退的脑血管疾病。丁苯酞（D1-NBP）是一种用于治疗缺血性脑血管疾病的神经保护药物，但其对WML的作用仍不清楚。本研究旨在探讨D1-NBP是否会影响WML模型中的认知功能并改善脱髓鞘。采用双侧颈动脉狭窄（BCAS）小鼠模型以及低葡萄糖和低氧（LGLO）处理的脑片培养。在BCAS后通过灌胃给予D1-NBP 28天，或在LGLO后以剂量50μm添加48小时。通过八臂放射状迷宫评估空间学习和记忆。使用透射电子显微镜（TEM）检测脱髓鞘。通过延时成像在培养的脑片中评估线粒体动力学。通过膜片钳技术评估突触功能。在BCAS小鼠中，观察到明显的脱髓鞘和认知衰退，而高剂量D1-NBP治疗（100mg/kg）可显著缓解两者。随着脱髓鞘，BCAS小鼠模型中轴突中的线粒体积累显著增加，但高剂量D1-NBP治疗后，线粒体积累减轻，线粒体的顺行/逆行运输增加。随着线粒体顺行/逆行运输的改善，培养的脑片中突触活性显著上调，而活性氧（ROS）生成显著减少。此外，我们确定突触结合蛋白（SNPH）为D1-NBP的下游靶点。SNPH的过表达介导了D1-NBP减轻轴突线粒体积累的作用。总之，D1-NBP治疗通过促进线粒体动力学显著缓解了WML模型中的脱髓鞘并改善了空间学习和记忆。D1-NBP的这些神经保护作用是通过抑制线粒体成拱蛋白SNPH介导的，这为WML提供了一个潜在的治疗靶点。
