Document Details
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Document Type |
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Thesis |
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Document Title |
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Studying The Molecular and Behavioral Mechanisms of Novel Therapeutics Combinations in Multiple Sclerosis Disease دراسة الآليات الجزيئية والسلوكية لتراكيب علاجية جديدة في مرض التصلب المتعدد |
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Subject |
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Faculty of Science |
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Document Language |
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Arabic |
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Abstract |
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Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) that destroys the myelin sheath, accompanied by a wide range of clinical complications that negatively impact the quality of life. Stimulation of remyelination is critical for treating MS to alleviate symptoms and protect the myelin sheath from further damage. The current study aimed to investigate the possible therapeutic effects of combining vitamin D3 (Vit D3) and siponimod (Sipo) on enhancing remyelination and modulating microglia phenotypes in the cuprizone (CPZ) demyelination mouse model. The study was divided into two stages; demyelination (first five weeks) and remyelination (last four weeks). In the first five weeks, 85 mice were randomly divided into two groups, control (n=20, standard rodent chow) and CPZ (n=65, 0.3% CPZ mixed with chow for six weeks, followed by three weeks of standard rodent chow). At the end of week 5, the CPZ group was re-divided into four groups (n=14) for remyelination stages; untreated CPZ (0.2 ml of carboxy methyl cellulose orally), CPZ+Vit D3 (800 IU/kg Vit D3 orally), CPZ+ Sipo (1.5 mg/kg Sipo orally), and CPZ+Vit D3 (800 IU/kg Vit D3) + Sipo (1.5 mg/kg Sipo) orally. One week overlapped between CPZ exposure and drug treatment, to be sure that remyelination was brought on by the medications and not by spontaneous withdrawal of CPZ. Various behavioral tests were performed to evaluate motor, anxiety, and memory performance. These include the open field, grip strength meter, rotarod, elevated plus maze, Y-maze, and novel object recognition tests. Luxol Fast Blue (LFB) staining, and the expression level of target genes were assessed in the corpus callosum (CC). In addition, histopathological changes in the prefrontal cortex (PFC) and hippocampus (HIP) were examined by hematoxylin and eosin (H & E). A molecular docking was used to predict the action of Vit D3 and Sipo on inhibiting iNOS. The results showed that the combination of Vit D3 and Sipo improved locomotor activity in an open field test at the early remyelination stage and significantly improved grip strength in the grip strength meter test and motor coordination in the rotarod test at the late stage compared with CPZ. In addition, the combination also significantly promoted remyelination by increasing the expression of myelin basic protein (MBP) at the early and late remyelination stages. Moreover, the combination of these treatments significantly attenuated the degenerative changes in the PFC and HIP regions. In conclusion, these results demonstrate for the first time that a combination of Vit D3 and Sipo can enhance the remyelination process in the CPZ mouse model. This could help to improve the treatment of MS patients.
Key words: Multiple sclerosis, vitamin D3, Siponimod, cuprizone, remyelination |
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Supervisor |
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Prof. Ulfat Omar |
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Thesis Type |
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Doctorate Thesis |
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Publishing Year |
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1445 AH
2023 AD |
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Co-Supervisor |
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Prof. Maryam AL-Ghamdi |
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Added Date |
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Wednesday, December 20, 2023 |
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Researchers
| خلود مرزوق العتيبي | Alotaibi, Kholoud Marzooq | Researcher | Doctorate | |
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