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Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines
Published on: September 21, 2021
Dapsone reduced cuprizone-induced demyelination via targeting Nrf2 and IKB in C57BL/6 mice
Ahmad Reza Dehpour1,2, Ehsan Khaledi3, Tayebeh Noori4
1Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Objectives:
Multiple Sclerosis (MS) is an inflammatory disorder wherein the myelin of nerve cells in the central nervous system is damaged. In the current study, we assessed the effect of Dapsone (DAP) on the improvement of behavioral dysfunction and preservation of myelin in the cuprizone (CPZ) induced demyelination model via targeting Nrf2 and IKB.
Materials And Methods:
MS was induced in C57BL/6 mice through diet supplementation of CPZ (0.2%) for 6 weeks, and DAP (12.5 mg/kg/day; IP) was administered for the last 2 weeks of treatment. Pole test and rotarod performance test, LFB and H&E staining, and Immunohistochemistry (IHC) staining of p-Nrf2 and p-IKB were performed. Furthermore, superoxide dismutase (SOD) and nitrite were measured.
Results:
DAP treatment prevented body loss induced by CPZ (P<0.001). Pole test showed that CPZ increased latency time to fall (P<0.0001) but the latency to reach the floor in the DAP-CPZ group was significantly shorter (P<0.0001). Rotarod performance test showed the effect of CPZ in reducing fall time in the CPZ group (P<0.0014); however, DAP significantly increased fall time (P=0.0012). In LFB staining, DAP reduced demyelination induced by CPZ. CPZ significantly decreased p-Nrf2 and elevated p-IKB levels compared with the control group (P<0.0001), but in DAP-treated groups markedly modified these changes (P<0.0001). CPZ increased the brain nitrite levels and reduced SOD activity, but in DAP-treated considerably reversed CPZ-induced changes.
Conclusion:
These data support the suggestion that the beneficial properties of DAP on the CPZ-induced demyelination are mediated by targeting Nrf2 and NF-kB pathways.
Insights
Dapsone (DAP) treatment improved behavioral deficits and preserved myelin in a mouse model of Multiple Sclerosis (MS). DAP
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple Sclerosis (MS) is an inflammatory central nervous system disorder damaging myelin.
- The cuprizone (CPZ) mouse model mimics MS-like demyelination and associated behavioral dysfunction.
Purpose of the Study:
- To evaluate Dapsone's (DAP) efficacy in ameliorating behavioral deficits.
- To assess DAP's ability to preserve myelin in the CPZ-induced demyelination model.
- To investigate DAP's mechanism of action via Nrf2 and NF-kB pathways.
Main Methods:
- MS was induced in C57BL/6 mice using CPZ (0.2% diet).
- DAP (12.5 mg/kg/day) was administered during the final 2 weeks of CPZ treatment.
- Behavioral tests (Pole, Rotarod), myelin staining (LFB), and molecular analysis (p-Nrf2, p-IKB, SOD, nitrite) were performed.
Main Results:
- DAP treatment counteracted CPZ-induced body weight loss and improved performance in Pole and Rotarod tests.
- DAP significantly reduced demyelination, as evidenced by Luxol Fast Blue (LFB) staining.
- DAP modulated Nrf2 and NF-kB signaling pathways, increasing p-Nrf2 and decreasing p-IKB levels.
- DAP treatment reversed CPZ-induced alterations in brain superoxide dismutase (SOD) activity and nitrite levels.
Conclusions:
- Dapsone demonstrates significant neuroprotective effects in a mouse model of demyelination.
- The therapeutic benefits of DAP are attributed to its modulation of Nrf2 and NF-kB signaling pathways.
- DAP shows potential as a therapeutic agent for inflammatory demyelinating diseases like Multiple Sclerosis.
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