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

Daekwon Bae,Nina Ha,Soo Min Ko,Ji-Young Lee,Donghyeon Suh,Hee Seon Lim,Da Som Jeong,Jiyeon Baek,Jinsol Park,Taehee Kim,Woo-Chan Son

doi:10.1038/s41598-021-93232-6

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.

Highlights

Despite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects
In this study, mice were treated with CKD-506 at a dose range of 3–100 mg/kg bodyweight to examine the effective dose for the prophylactic regimen
The clinical scores were significantly lower, while the disease onset was significantly delayed in the groups treated with CKD-506 at doses of ≥ 30 mg/kg bodyweight than in the vehicle-treated group [Fig. 1a, Table 1; F(8, 144) = 62.65; p < 0.001; one-way Analysis of variance (ANOVA)]

Summary

Results

CKD‐506 alleviated the clinical symptoms of EAE in mice subjected to the prophylactic regimen. This study examined the extravasation of the Evans blue (EB) dye and the expression level of occludin, an endothelial tight junction protein, in the spinal cord to determine the effect of CKD-506 and fingolimod on BBB integrity in the vehicle group on day 21 post-EAE induction. The symptom severity in the CKD506-treated group on day 22 post-EAE induction was significantly lower than that in the vehicle-treated group after fingolimod was replaced with CKD-506 or vehicle on day 15 post-EAE induction [Fig. 6c; F(1, 280) = 13.47; p = 0.0003; two-way ANOVA] This suggests that CKD-506 delayed the exacerbation of the clinical symptoms in mice with EAE. The blood cytokine analysis of the EAE mice at 18 days after induction showed that the effect of CKD-506 on the levels of TNF-α persisted even after drug discontinuation [Supplementary data; F(4, 30) = 20.72; p < 0.0001; one-way ANOVA]. These findings demonstrate that CKD-506 could alleviate depression-like behavior by exerting therapeutic effects in the brain

Discussion

Methods

Therapeutic regimen

Treatment regimen to evaluate the mechanism of action