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Cu,Zn-Superoxide Dismutase has Minimal Effects Against Cuprizone-Induced Demyelination, Microglial Activation, and Neurogenesis Defects in the C57BL/6 Mouse Hippocampus

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Abstract

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.

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Funding

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Korean government (MSIP) (NRF-2018R1D1A1B07044543). This work was also supported by the Research Institute for Veterinary Science at the Seoul National University.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, South Korea

    Kyu Ri Hahn, Woosuk Kim, Hyo Young Jung, In Koo Hwang & Yeo Sung Yoon

  2. Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, 25457, South Korea

    Hyun Jung Kwon & Dae Won Kim

  3. Department of Biomedical Sciences, and Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, South Korea

    Hyun Jung Kwon

  4. Department of Anatomy, College of Veterinary Medicine, and Veterinary Science Research Institute, Konkuk University, Seoul, 05030, South Korea

    Woosuk Kim

  5. Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon, 34134, South Korea

    Hyo Young Jung

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Contributions

KRH., HJK., WK., HYJ., IKH., DWK., and YSY. conceived the study. KRH., HJK., DWK., and YSY. designed the study and prepared the manuscript. KRH., WK., and HYJ. conducted animal experiments. HJK. and DWK. conducted biochemical experiments. IKH. participated in the design and discussion of animal studies. All authors read and approved the manuscript, all data were generated in-house.

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Correspondence to Yeo Sung Yoon.

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Hahn, K.R., Kwon, H.J., Kim, W. et al. Cu,Zn-Superoxide Dismutase has Minimal Effects Against Cuprizone-Induced Demyelination, Microglial Activation, and Neurogenesis Defects in the C57BL/6 Mouse Hippocampus. Neurochem Res 48, 2138–2147 (2023). https://doi.org/10.1007/s11064-023-03886-z

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