CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis

• Published in: Scientific reports Vol. 11; no. 1; pp. 14466 - 16
• Main Authors: Bae, Daekwon, Lee, Ji-Young, Ha, Nina, Park, Jinsol, Baek, Jiyeon, Suh, Donghyeon, Lim, Hee Seon, Ko, Soo Min, Kim, Taehee, Som Jeong, Da, Son, Woo-Chan
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 14.07.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Antidepressive Agents - administration & dosage; Antidepressive Agents - pharmacology; Autoimmune diseases; Blood-brain barrier; Blood-Brain Barrier - drug effects; CD11b antigen; CD4 antigen; CD45 antigen; Cell Proliferation - drug effects; Cytokines - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Encephalomyelitis, Autoimmune, Experimental - chemically induced; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - etiology; Experimental allergic encephalomyelitis; Female; Fingolimod Hydrochloride - pharmacology; Histone Deacetylase 6 - antagonists & inhibitors; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - pharmacology; Inflammation; Lymphocytes T; Macrophages; Macrophages - drug effects; Macrophages - pathology; Mice; Mice, Inbred C57BL; Microglia; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - etiology; Myelin; Myelin-Oligodendrocyte Glycoprotein - toxicity; Spinal cord; Spinal Cord - drug effects; Spinal Cord - physiopathology; Splenocytes; T-Lymphocytes - drug effects; T-Lymphocytes - pathology; γ-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-93232-6

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 glycoprotein (MOG )-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 MOG -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.