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Updated: Jun 28, 2025
Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines
Published on: September 21, 2021
5Z-7-Oxozaenol attenuates cuprizone-induced demyelination in mice through microglia polarization regulation
Shiyu Chen1,2, Siyao Liu2, Yalun Huang1
1Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Introduction:
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.
Methods:
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.
Results:
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.
Conclusion:
These findings suggest that inhibiting TAK1 may be an effective approach for treating demyelinating diseases.
Insights
Inhibiting Transforming growth factor beta activated kinase 1 (TAK1) with 5Z-7-Oxozaenol (OZ) protected against demyelination and behavioral deficits in a mouse model. This suggests TAK1 inhibition is a promising therapeutic strategy for demyelinating diseases.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Demyelination causes axonal degeneration and neural loss in multiple sclerosis (MS).
- Transforming growth factor beta activated kinase 1 (TAK1) is crucial in immune and inflammatory signaling.
- Microglia TAK1 knockout inhibits neuroinflammation and improves MS outcomes, but its role in demyelination is unclear.
Purpose of the Study:
- To investigate the effect of inhibiting TAK1 on demyelination.
- To evaluate the therapeutic potential of 5Z-7-Oxozaenol (OZ) in a cuprizone-induced demyelination model.
Main Methods:
- Cuprizone (CPZ) induced demyelination in C57BL/6J mice over 5 weeks.
- Mice were treated with vehicle or OZ (15 μg/30 μg) intraperitoneally twice weekly.
- Evaluations included histology, behavioral tests, Western blot, RT-PCR, and ELISA to assess demyelination, oligodendrocyte loss, TAK1 signaling, microglia phenotype, and cytokine levels.
Main Results:
- OZ treatment protected against CPZ-induced myelin loss and behavioral impairment.
- OZ administration rescued oligodendrocyte loss and inhibited JNK, p65, and p38 pathway activation.
- OZ shifted microglia from M1 to M2 phenotype, increased BDNF expression, and modulated pro- and anti-inflammatory cytokines.
Conclusions:
- Inhibiting TAK1 with OZ effectively attenuates demyelination and associated behavioral deficits.
- TAK1 inhibition demonstrates potential as a therapeutic strategy for demyelinating diseases like MS.
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