CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis
Abstract Despite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects. Here, the therapeutic potential of CKD-506, a novel HDAC6-selective inhibitor, against MS was evaluated in mice with myelin oligodendrocyte glycoprotein35...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-93232-6 |
| _version_ | 1818433946898137088 |
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| author | Daekwon Bae Ji-Young Lee Nina Ha Jinsol Park Jiyeon Baek Donghyeon Suh Hee Seon Lim Soo Min Ko Taehee Kim Da Som Jeong Woo-chan Son |
| author_facet | Daekwon Bae Ji-Young Lee Nina Ha Jinsol Park Jiyeon Baek Donghyeon Suh Hee Seon Lim Soo Min Ko Taehee Kim Da Som Jeong Woo-chan Son |
| author_sort | Daekwon Bae |
| collection | DOAJ |
| description | Abstract Despite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects. Here, the therapeutic potential of CKD-506, a novel HDAC6-selective inhibitor, against MS was evaluated in mice with myelin oligodendrocyte glycoprotein35–55 (MOG35–55)-induced experimental autoimmune encephalitis (EAE) under various treatment regimens. CKD-506 exerted prophylactic and therapeutic effects by regulating peripheral immune responses and maintaining blood–brain barrier (BBB) integrity. In MOG35–55-re-stimulated splenocytes, CKD-506 decreased proliferation and downregulated the expression of IFN-γ and IL-17A. CKD-506 downregulated the levels of pro-inflammatory cytokines in the blood of EAE mice. Additionally, CKD-506 decreased the leakage of intravenously administered Evans blue into the spinal cord; CD4+ T cells and CD4−CD11b+CD45+ macrophage/microglia in the spinal cord was also decreased. Moreover, CKD-506 exhibited therapeutic efficacy against MS, even when drug administration was discontinued from day 15 post-EAE induction. Disease exacerbation was not observed when fingolimod was changed to CKD-506 from day 15 post-EAE induction. CKD-506 alleviated depression-like behavior at the pre-symptomatic stage of EAE. In conclusion, CKD-506 exerts therapeutic effects by regulating T cell- and macrophage-mediated peripheral immune responses and strengthening BBB integrity. Our results suggest that CKD-506 is a potential therapeutic agent for MS. |
| first_indexed | 2024-12-14T16:29:11Z |
| format | Article |
| id | doaj.art-5f77b10b118742ed8e9fb83f53cbdc9f |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T16:29:11Z |
| publishDate | 2021-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-5f77b10b118742ed8e9fb83f53cbdc9f2022-12-21T22:54:37ZengNature PortfolioScientific Reports2045-23222021-07-0111111610.1038/s41598-021-93232-6CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosisDaekwon Bae0Ji-Young Lee1Nina Ha2Jinsol Park3Jiyeon Baek4Donghyeon Suh5Hee Seon Lim6Soo Min Ko7Taehee Kim8Da Som Jeong9Woo-chan Son10Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Pharmacology, CKD Research Institute, CKD Pharmaceutical CoDepartment of Pharmacology, CKD Research Institute, CKD Pharmaceutical CoDepartment of Pharmacology, CKD Research Institute, CKD Pharmaceutical CoDepartment of Pharmacology, CKD Research Institute, CKD Pharmaceutical CoDepartment of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Pathology, Asan Medical Center, University of Ulsan College of MedicineAbstract Despite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects. Here, the therapeutic potential of CKD-506, a novel HDAC6-selective inhibitor, against MS was evaluated in mice with myelin oligodendrocyte glycoprotein35–55 (MOG35–55)-induced experimental autoimmune encephalitis (EAE) under various treatment regimens. CKD-506 exerted prophylactic and therapeutic effects by regulating peripheral immune responses and maintaining blood–brain barrier (BBB) integrity. In MOG35–55-re-stimulated splenocytes, CKD-506 decreased proliferation and downregulated the expression of IFN-γ and IL-17A. CKD-506 downregulated the levels of pro-inflammatory cytokines in the blood of EAE mice. Additionally, CKD-506 decreased the leakage of intravenously administered Evans blue into the spinal cord; CD4+ T cells and CD4−CD11b+CD45+ macrophage/microglia in the spinal cord was also decreased. Moreover, CKD-506 exhibited therapeutic efficacy against MS, even when drug administration was discontinued from day 15 post-EAE induction. Disease exacerbation was not observed when fingolimod was changed to CKD-506 from day 15 post-EAE induction. CKD-506 alleviated depression-like behavior at the pre-symptomatic stage of EAE. In conclusion, CKD-506 exerts therapeutic effects by regulating T cell- and macrophage-mediated peripheral immune responses and strengthening BBB integrity. Our results suggest that CKD-506 is a potential therapeutic agent for MS.https://doi.org/10.1038/s41598-021-93232-6 |
| spellingShingle | Daekwon Bae Ji-Young Lee Nina Ha Jinsol Park Jiyeon Baek Donghyeon Suh Hee Seon Lim Soo Min Ko Taehee Kim Da Som Jeong Woo-chan Son CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis Scientific Reports |
| title | CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis |
| title_full | CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis |
| title_fullStr | CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis |
| title_full_unstemmed | CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis |
| title_short | CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis |
| title_sort | ckd 506 a novel hdac6 selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis |
| url | https://doi.org/10.1038/s41598-021-93232-6 |
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