Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, South Korea.
Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, 25457, South Korea.
Neurochem Res. 2023 Jul;48(7):2138-2147. doi: 10.1007/s11064-023-03886-z. Epub 2023 Feb 20.
Cuprizone causes consistent demyelination and oligodendrocyte damage in the mouse brain. Cu,Zn-superoxide dismutase 1 (SOD1) has neuroprotective potential against various neurological disorders, such as transient cerebral ischemia and traumatic brain injury. In this study, we investigated whether SOD1 has neuroprotective effects against cuprizone-induced demyelination and adult hippocampal neurogenesis in C57BL/6 mice, using the PEP-1-SOD1 fusion protein to facilitate the delivery of SOD1 protein into hippocampal neurons. Eight weeks feeding of cuprizone-supplemented (0.2%) diets caused a significant decrease in myelin basic protein (MBP) expression in the stratum lacunosum-moleculare of the CA1 region, the polymorphic layer of the dentate gyrus, and the corpus callosum, while ionized calcium-binding adapter molecule 1 (Iba-1)-immunoreactive microglia showed activated and phagocytic phenotypes. In addition, cuprizone treatment reduced proliferating cells and neuroblasts as shown using Ki67 and doublecortin immunostaining. Treatment with PEP-1-SOD1 to normal mice did not show any significant changes in MBP expression and Iba-1-immunoreactive microglia. However, Ki67-positive proliferating cells and doublecortin-immunoreactive neuroblasts were significantly decreased. Simultaneous treatment with PEP-1-SOD1 and cuprizone-supplemented diets did not ameliorate the MBP reduction in these regions, but mitigated the increase of Iba-1 immunoreactivity in the corpus callosum and alleviated the reduction of MBP in corpus callosum and proliferating cells, not neuroblasts, in the dentate gyrus. In conclusion, PEP-1-SOD1 treatment only has partial effects to reduce cuprizone-induced demyelination and microglial activation in the hippocampus and corpus callosum and has minimal effects on proliferating cells in the dentate gyrus.
铜锌超氧化物歧化酶 1（SOD1）对各种神经紊乱具有神经保护作用，如短暂性脑缺血和创伤性脑损伤。在这项研究中，我们使用 PEP-1-SOD1 融合蛋白来促进 SOD1 蛋白递送至海马神经元，以调查 SOD1 是否对 C57BL/6 小鼠中的杯状醇诱导的脱髓鞘和成年海马神经发生具有神经保护作用。8 周喂食补充杯状醇（0.2%）的饮食会导致 CA1 区腔隙分子层、齿状回多形层和胼胝体中髓鞘碱性蛋白（MBP）表达显著减少，而离子钙结合衔接分子 1（Iba-1）免疫反应性小胶质细胞表现出激活和吞噬表型。此外，杯状醇处理减少了增殖细胞和神经母细胞，如 Ki67 和双皮质素免疫染色所示。PEP-1-SOD1 处理正常小鼠不会导致 MBP 表达和 Iba-1 免疫反应性小胶质细胞发生任何显著变化。然而，Ki67 阳性增殖细胞和双皮质素免疫反应性神经母细胞明显减少。同时给予 PEP-1-SOD1 和补充杯状醇的饮食并不能改善这些区域的 MBP 减少，但减轻了胼胝体中 Iba-1 免疫反应性的增加，并缓解了齿状回中 MBP 的减少和增殖细胞的减少，而不是神经母细胞。总之，PEP-1-SOD1 治疗仅对减少海马和胼胝体中杯状醇诱导的脱髓鞘和小胶质细胞激活具有部分作用，对齿状回中的增殖细胞作用最小。
