Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of General Practice, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Brain Behav. 2024 Apr;14(4):e3487. doi: 10.1002/brb3.3487.
Demyelination is a key factor in axonal degeneration and neural loss, leading to disability in multiple sclerosis (MS) patients. Transforming growth factor beta activated kinase 1 (TAK1) is a critical molecule involved in immune and inflammatory signaling pathways. Knockout of microglia TAK1 can inhibit autoimmune inflammation of the brain and spinal cord and improve the outcome of MS. However, it is unclear whether inhibiting TAK1 can alleviate demyelination.
Eight-week-old male c57bl/6j mice were randomly divided into five groups: (a) the control group, (b) the group treated with cuprizone (CPZ) only, (c) the group treated with 5Z-7-Oxozaenol (OZ) only, and (d) the group treated with both cuprizone and 15 μg/30 μg OZ. Demyelination in the mice of this study was induced by administration of CPZ (ig) at a daily dose of 400 mg/kg for consecutive 5 weeks. OZ was intraperitoneally administered at mentioned doses twice a week, starting from week 3 after beginning cuprizone treatment. Histology, rotarod test, grasping test, pole test, Western blot, RT-PCR, and ELISA were used to evaluate corpus callosum demyelination, behavioral impairment, oligodendrocyte differentiation, TAK1 signaling pathway expression, microglia, and related cytokines.
Our results demonstrated that OZ protected against myelin loss and behavior impairment caused by CPZ. Additionally, OZ rescued the loss of oligodendrocytes in CPZ-induced mice. OZ inhibited the activation of JNK, p65, and p38 pathways, transformed M1 polarized microglia into M2 phenotype, and increased brain-derived neurotrophic factor (BDNF) expression to attenuate demyelination in CPZ-treated mice. Furthermore, OZ reduced the expression of proinflammatory cytokines and increases anti-inflammatory cytokines in CPZ-treated mice.
These findings suggest that inhibiting TAK1 may be an effective approach for treating demyelinating diseases.
脱髓鞘是轴突变性和神经丢失的一个关键因素，导致多发性硬化症（MS）患者残疾。转化生长因子β激活激酶 1（TAK1）是参与免疫和炎症信号通路的关键分子。小胶质细胞 TAK1 敲除可以抑制脑和脊髓的自身免疫炎症，并改善 MS 的预后。然而，尚不清楚抑制 TAK1 是否可以减轻脱髓鞘。
将 8 周龄雄性 C57BL/6J 小鼠随机分为五组：（a）对照组，（b）仅用 CPZ 处理组，（c）仅用 5Z-7-Oxozaenol（OZ）处理组，（d）同时用 CPZ 和 15μg/30μg OZ 处理组。该研究通过连续 5 周每天给予 CPZ（ig）400mg/kg 的剂量来诱导小鼠脱髓鞘。OZ 以所述剂量每周两次腹膜内给药，从 CPZ 处理开始后的第 3 周开始。使用组织学、转棒试验、抓握试验、棒试验、Western blot、RT-PCR 和 ELISA 来评估胼胝体脱髓鞘、行为障碍、少突胶质细胞分化、TAK1 信号通路表达、小胶质细胞和相关细胞因子。
我们的结果表明，OZ 可防止 CPZ 引起的髓鞘丢失和行为障碍。此外，OZ 挽救了 CPZ 诱导的小鼠中少突胶质细胞的丢失。OZ 抑制 JNK、p65 和 p38 途径的激活，将 M1 极化的小胶质细胞转化为 M2 表型，并增加脑源性神经营养因子（BDNF）的表达，以减轻 CPZ 处理小鼠的脱髓鞘。此外，OZ 降低了 CPZ 处理小鼠中促炎细胞因子的表达并增加了抗炎细胞因子的表达。
这些发现表明抑制 TAK1 可能是治疗脱髓鞘疾病的有效方法。
