Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes

Abstract Background Silymarin (SMN), a polyphenolic flavonoid, is involved in multiple bioactive functions including anti-inflammation. Pretreatment with SMN demonstrated chondroprotection against tumour necrosis factor-alpha (TNF-α) stimulation in a chondrocyte cell line. However, pre- and posttreatment with phytochemicals have varying effects on osteoarthritis (OA) chondrocytes, and the therapeutic potential of SMN after catabolic cytokine stimulation is not fully elucidated. Methods The cytotoxicity of SMN (12.5, 25, 50 and 100 μM) was evaluated in human primary chondrocytes. The chondrocytes were supplemented with SMN (25 and 50 μM) after interleukin-1beta (IL-1β) stimulation. The mRNA expression and protein production of catabolic/anabolic cytokines as well as extracellular matrix (ECM) components were evaluated. Results High-dose SMN (100 μM) impaired the mitochondrial activity in chondrocytes, and 50 μM SMN further caused cell death in IL-1β-stimulated cells. The addition of 25 μM SMN ameliorated cell senescence; downregulated the catabolic genes of inducible nitric oxide synthase, IL-1β, TNF-α, matrix metalloproteinase-3 (MMP-3), MMP-9 and MMP-13; upregulated the anabolic genes of tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen type II alpha 1; and restored the expression of chondrogenic phenotype genes SOX9 and sirtuin-1 (Sirt1). In addition, the production of IL-1β, MMP-3 and MMP-9 decreased with an increase in TIMP-1 secretion. However, the mRNA levels of IL-6, IL-8 and IL-10 and protein production remained high. The addition of nicotinamide, a Sirt1 inhibitor, downregulated SOX9 and attenuated the therapeutic effects of SMN on IL-1β-stimulated chondrocytes. Conclusion SMN regulates the chondrocyte phenotype through Sirt1 and SOX9 to improve ECM homeostasis and may serve as a complementary therapy for early-stage knee OA.

Download Full-text

Extracellular Vesicles from Mesenchymal Stromal Cells for the Treatment of Inflammation-Related Conditions

International Journal of Molecular Sciences ◽

10.3390/ijms22063023 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3023

Author(s):

Sean T. Ryan ◽

Elham Hosseini-Beheshti ◽

Dinara Afrose ◽

Xianting Ding ◽

Binbin Xia ◽

...

Keyword(s):

Extracellular Vesicles ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Animal Studies ◽

Therapeutic Potential ◽

Early Stage ◽

Small Animal ◽

Therapeutic Effects ◽

Anti Inflammatory

Over the past two decades, mesenchymal stromal cells (MSCs) have demonstrated great potential in the treatment of inflammation-related conditions. Numerous early stage clinical trials have suggested that this treatment strategy has potential to lead to significant improvements in clinical outcomes. While promising, there remain substantial regulatory hurdles, safety concerns, and logistical issues that need to be addressed before cell-based treatments can have widespread clinical impact. These drawbacks, along with research aimed at elucidating the mechanisms by which MSCs exert their therapeutic effects, have inspired the development of extracellular vesicles (EVs) as anti-inflammatory therapeutic agents. The use of MSC-derived EVs for treating inflammation-related conditions has shown therapeutic potential in both in vitro and small animal studies. This review will explore the current research landscape pertaining to the use of MSC-derived EVs as anti-inflammatory and pro-regenerative agents in a range of inflammation-related conditions: osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, cardiovascular disease, and preeclampsia. Along with this, the mechanisms by which MSC-derived EVs exert their beneficial effects on the damaged or degenerative tissues will be reviewed, giving insight into their therapeutic potential. Challenges and future perspectives on the use of MSC-derived EVs for the treatment of inflammation-related conditions will be discussed.

Download Full-text

AB0071 THERAPEUTIC EFFECTS OF BONE MARROW MESENCHYMAL STEM CELLS-DERIVED EXOSOMES ON OSTEOARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6040 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1336.3-1336

Author(s):

C. Dong ◽

Y. Liu ◽

A. Deng ◽

J. Ji ◽

W. Zheng ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Therapeutic Potential ◽

Early Stage ◽

Cruciate Ligament ◽

Joint Damage ◽

Therapeutic Effects ◽

Chondrocyte Phenotype

Background:Mesenchymal stem cells (MSCs) have shown chondroprotective effects in clinical models of osteoarthritis (OA)[1].Objectives:The study aimed to investigate the therapeutic potential of exosomes from human bone marrow MSCs (BM-MSCs) in alleviating OA.Methods:The anterior cruciate ligament transection (ACLT) anddestabilization of the medial meniscus (DMM) surgery were performed on the knee joints of a rat OA model, followed by intra-articular injection of BM-MSCs or their exosomes. The beneficial effects were evaluated by histological staining, OARSI scores and micro-CT. Furthermore, BM-MSCs-derived exosomes were administrated to primary human chondrocytes to observe the functional and molecular alterations. In addition, lncRNA MEG3 were investigated in chondrocytes to explore the biological contents accounting for anti-OA effects of BM-MSCs-derived exosomes.Results:Based on the observation in the rat OA model, both of BM-MSCs and BM-MSCs-derived exosomes alleviated cartilage destruction, reduced joint damage and restored the trabecular bone of OA rats. In addition,in vitroassays showed that BM-MSCs- exosomes could maintain the chondrocyte phenotype by increasing collagen type II synthesis and inhibiting IL-1β- induced senescence and apoptosis. Furthermore, exosomal lncRNA MEG3 also reduced the senescence and apoptosis of chondrocytes induced by IL-1β, indicating that lncRNA MEG3 might partially account for the anti-OA effects of BM-MSC exosomes.Conclusion:The exosomes from BM-MSCs exerted beneficial therapeutic effects on OA by reducing the senescence and apoptosis of chondrocytes, suggesting that MSCs-derived exosomes might provide a candidate therapy for OA treatment.References:[1]Mckinney J M, Doan T N, Wang L, et al. Therapeutic efficacy of intra-articular delivery of encapsulated human mesenchymal stem cells on early stage osteoarthritis[J]. Eur Cell Mater, 2019, 37: 42-59.Disclosure of Interests:None declared

Download Full-text

TIMP-1 As a Promising Therapeutic Indicator for the Intestinal Inflammation and Fibrosis.

10.21203/rs.3.rs-530142/v1 ◽

2021 ◽

Author(s):

Keisuke Sato ◽

Hideyuki Suzuki ◽

Hideaki Karasawa ◽

Akihiro Yamamura ◽

Taiki Kajiwara ◽

...

Keyword(s):

Intestinal Inflammation ◽

Human Fibroblasts ◽

Major Complication ◽

Tissue Inhibitor Of Metalloproteinase ◽

Therapeutic Effects ◽

Mrna Levels ◽

Intestinal Tissue ◽

Intestinal Fibrosis ◽

Tnf Α ◽

Anti Inflammatory

Abstract Background: Intestinal fibrosis is a major complication of inflammatory bowel disease (IBD), which can be prevented with anti-inflammatory therapies. However, inflammatory biomarkers do not necessarily reflect the progression of fibrosis, and hence, an indicator that reflects the therapeutic effects of available anti-inflammatory drugs on fibrosis is needed. This study shows that tissue inhibitor of metalloproteinase-1 (TIMP-1) is a potential therapeutic indicator for ongoing intestinal fibrosis in IBD patients.Methods: TIMP-1 mRNA levels in human myofibroblasts were measured, and TIMP-1 expression in the intestine of 10 Crohn’s disease (CD) patients was examined by immunohistochemistry. Colitis was induced in C57BL/6 mice by administration of 1.5% dextran sodium sulfate for 7 days; then, the mice were treated with anti-TNF-α antibody or phosphate-buffered saline for 14 days. Intestinal fibrosis was evaluated by Masson’s trichrome staining, and TIMP-1 mRNA levels in the intestinal tissue and plasma TIMP-1 levels were measured.Results: TIMP-1 expression in human fibroblasts increased after differentiation into myofibroblasts. TIMP-1 expression in CD intestinal tissue was significantly higher in the inflammation area than in the fibrotic or normal areas. In a murine colitis mode in which TIMP-1 mRNA levels were increased, anti-TNF-α antibody administration significantly attenuated inflammation and fibrosis assessed by a reduction in TIMP-1 mRNA levels in intestinal tissue and plasma TIMP-1 levels.Conclusions: The results in this study show that TIMP-1 is a potential new biomarker that could be used to assess the effectivity of different therapeutic strategies for intestinal inflammation and fibrosis in IBD patients.

Download Full-text

Hyaluronic acid optimizes therapeutic effects of Hydrogen peroxide-induced oxidative stress on breast cancer

10.21203/rs.3.rs-21485/v1 ◽

2020 ◽

Author(s):

Ardeshir Abbasi ◽

Nafiseh Pakravan ◽

Zuhair Hassan

Keyword(s):

Oxidative Stress ◽

Hyaluronic Acid ◽

Cancer Cells ◽

Mononuclear Cells ◽

Phase Cell ◽

High Dose ◽

Therapeutic Effects ◽

Mrna Levels ◽

Dependent Manner

Abstract Background and Purpose: Distinguishing the multiple effects of reactive oxygen species (ROS) on cancer cells is important to understand their role in tumour biology. Conversely, elevated levels of ROS-induced oxidative stress can induce cancer cell death. However, some anti-oxidative or ROS-mediated oxidative therapies have also yielded beneficial effects.Experimental approach: To better define the effects of oxidative stress, in vitro experiments were conducted on 4T1 and splenic mononuclear cells (MNCs) under hypoxic and normoxic conditions. Furthermore, H2O2 [10-1000μM], was used as a ROS source alone or in combination with hyaluronic acid (HA), which is frequently used as drug delivery vehicle.Key Results: Our results indicate that treatment of cancer cells with H2O2+HA was significantly more effective than H2O2 alone. In addition, treatment with H2O2+HA led to increased apoptosis, decreased proliferation, and multi-phase cell cycle arrest in 4T1 cells in a dose-dependent manner under normoxic or hypoxic conditions. Also, migratory tendency and the mRNA levels of VEGF, and MMP-2,9 were significantly decreased. Of note, HA treatment combined with 100-1000μM H2O2+ caused more damage to MNCs as compared to treatment with lower concentrations [10-50μM]. Based on these results we propose to administer high dose H2O2+HA [100-1000μM] for intra-tumoral injection and low doses for systemic administration.Conclusions & Implications: Intra-tumoral route could have toxic and inhibitory effects not only on the tumour but also on residential myeloid cells defending it, whereas systemic treatment could stimulate peripheral immune responses against the tumour. More in vivo research is required to confirm this hypothesis.

Download Full-text

Therapeutic Potential of Dental Pulp Stem Cells and Leukocyte- and Platelet-Rich Fibrin for Osteoarthritis

Cells ◽

10.3390/cells9040980 ◽

2020 ◽

Vol 9 (4) ◽

pp. 980

Author(s):

Melissa Lo Monaco ◽

Pascal Gervois ◽

Joel Beaumont ◽

Peter Clegg ◽

Annelies Bronckaers ◽

...

Keyword(s):

Stem Cells ◽

Dental Pulp ◽

Chondrogenic Differentiation ◽

Articular Chondrocytes ◽

Therapeutic Potential ◽

3D Culture ◽

Dental Pulp Stem Cells ◽

Mrna Levels ◽

Platelet Rich Fibrin

Osteoarthritis (OA) is a degenerative and inflammatory joint disorder with cartilage loss. Dental pulp stem cells (DPSCs) can undergo chondrogenic differentiation and secrete growth factors associated with tissue repair and immunomodulation. Leukocyte- and platelet-rich fibrin (L-PRF) emerges in regenerative medicine because of its growth factor content and fibrin matrix. This study evaluates the therapeutic application of DPSCs and L-PRF in OA via immunomodulation and cartilage regeneration. Chondrogenic differentiation of DPSCs, with or without L-PRF exudate (ex) and conditioned medium (CM), and of bone marrow-mesenchymal stem cells was compared. These cells showed differential chondrogenesis. L-PRF was unable to increase cartilage-associated components. Immature murine articular chondrocytes (iMACs) were cultured with L-PRF ex, L-PRF CM, or DPSC CM. L-PRF CM had pro-survival and proliferative effects on unstimulated and cytokine-stimulated iMACs. L-PRF CM stimulated the release of IL-6 and PGE2, and increased MMP-13, TIMP-1 and IL-6 mRNA levels in cytokine-stimulated iMACs. DPSC CM increased the survival and proliferation of unstimulated iMACs. In cytokine-stimulated iMACs, DPSC CM increased TIMP-1 gene expression, whereas it inhibited nitrite release in 3D culture. We showed promising effects of DPSCs in an in vitro OA model, as they undergo chondrogenesis in vitro, stimulate the survival of chondrocytes and have immunomodulatory effects.

Download Full-text

Effects of Extracellular Vesicles Derived from Mesenchymal Stem/Stromal Cells on Liver Diseases

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190308123714 ◽

2019 ◽

Vol 14 (5) ◽

pp. 442-452 ◽

Cited By ~ 1

Author(s):

Wenjie Zheng ◽

Yumin Yang ◽

Russel Clive Sequeira ◽

Colin E. Bishop ◽

Anthony Atala ◽

...

Keyword(s):

Regenerative Medicine ◽

Extracellular Vesicles ◽

Stromal Cells ◽

Liver Diseases ◽

Therapeutic Potential ◽

Mechanisms Of Action ◽

Therapeutic Effects ◽

Chronic Liver Injury ◽

Mediated Effects ◽

Therapeutic Benefits

Therapeutic effects of Mesenchymal Stem/Stromal Cells (MSCs) transplantation have been observed in various disease models. However, it is thought that MSCs-mediated effects largely depend on the paracrine manner of secreting cytokines, growth factors, and Extracellular Vesicles (EVs). Similarly, MSCs-derived EVs also showed therapeutic benefits in various liver diseases through alleviating fibrosis, improving regeneration of hepatocytes, and regulating immune activity. This review provides an overview of the MSCs, their EVs, and their therapeutic potential in treating various liver diseases including liver fibrosis, acute and chronic liver injury, and Hepatocellular Carcinoma (HCC). More specifically, the mechanisms by which MSC-EVs induce therapeutic benefits in liver diseases will be covered. In addition, comparisons between MSCs and their EVs were also evaluated as regenerative medicine against liver diseases. While the mechanisms of action and clinical efficacy must continue to be evaluated and verified, MSCs-derived EVs currently show tremendous potential and promise as a regenerative medicine treatment for liver disease in the future.

Download Full-text

Therapeutic Potential of Amniotic Fluid Derived Mesenchymal Stem Cells Based on their Differentiation Capacity and Immunomodulatory Properties

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190222201749 ◽

2019 ◽

Vol 14 (4) ◽

pp. 327-336 ◽

Cited By ~ 9

Author(s):

Carl R. Harrell ◽

Marina Gazdic ◽

Crissy Fellabaum ◽

Nemanja Jovicic ◽

Valentin Djonov ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Animal Models ◽

Amniotic Fluid ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Therapeutic Effects ◽

Differentiation Potential ◽

Differentiation Capacity ◽

Cell Based Therapy

Background: Amniotic Fluid Derived Mesenchymal Stem Cells (AF-MSCs) are adult, fibroblast- like, self-renewable, multipotent stem cells. During the last decade, the therapeutic potential of AF-MSCs, based on their huge differentiation capacity and immunomodulatory characteristics, has been extensively explored in animal models of degenerative and inflammatory diseases. Objective: In order to describe molecular mechanisms responsible for the therapeutic effects of AFMSCs, we summarized current knowledge about phenotype, differentiation potential and immunosuppressive properties of AF-MSCs. Methods: An extensive literature review was carried out in March 2018 across several databases (MEDLINE, EMBASE, Google Scholar), from 1990 to present. Keywords used in the selection were: “amniotic fluid derived mesenchymal stem cells”, “cell-therapy”, “degenerative diseases”, “inflammatory diseases”, “regeneration”, “immunosuppression”. Studies that emphasized molecular and cellular mechanisms responsible for AF-MSC-based therapy were analyzed in this review. Results: AF-MSCs have huge differentiation and immunosuppressive potential. AF-MSCs are capable of generating cells of mesodermal origin (chondrocytes, osteocytes and adipocytes), neural cells, hepatocytes, alveolar epithelial cells, insulin-producing cells, cardiomyocytes and germ cells. AF-MSCs, in juxtacrine or paracrine manner, regulate proliferation, activation and effector function of immune cells. Due to their huge differentiation capacity and immunosuppressive characteristic, transplantation of AFMSCs showed beneficent effects in animal models of degenerative and inflammatory diseases of nervous, respiratory, urogenital, cardiovascular and gastrointestinal system. Conclusion: Considering the fact that amniotic fluid is obtained through routine prenatal diagnosis, with minimal invasive procedure and without ethical concerns, AF-MSCs represents a valuable source for cell-based therapy of organ-specific or systemic degenerative and inflammatory diseases.

Download Full-text

Relapse After Early-Stage, Favorable Hodgkin Lymphoma: Disease Characteristics and Outcomes With Conventional or High-Dose Chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.20.00947 ◽

2021 ◽

Vol 39 (2) ◽

pp. 107-115

Author(s):

Paul J. Bröckelmann ◽

Horst Müller ◽

Teresa Guhl ◽

Karolin Behringer ◽

Michael Fuchs ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Early Stage ◽

High Dose Chemotherapy ◽

Sensitivity Analyses ◽

High Dose ◽

Second Line ◽

Second Line Therapy ◽

Line Therapy ◽

Significant Difference ◽

First Diagnosis

PURPOSE We evaluated disease and treatment characteristics of patients with relapse after risk-adapted first-line treatment of early-stage, favorable, classic Hodgkin lymphoma (ES-HL). We compared second-line therapy with high-dose chemotherapy and autologous stem cell transplantation (ASCT) or conventional chemotherapy (CTx). METHODS We analyzed patients with relapse after ES-HL treated within the German Hodgkin Study Group HD10+HD13 trials. We compared, by Cox proportional hazards regression, progression-free survival (PFS) after relapse (second PFS) treated with either ASCT or CTx and performed sensitivity analyses with overall survival (OS) from relapse and Kaplan-Meier statistics. RESULTS A total of 174 patients’ disease relapsed after treatment in the HD10 (n = 53) and HD13 (n = 121) trials. Relapse mostly occurred > 12 months after first diagnosis, predominantly with stage I-II disease. Of 172 patients with known second-line therapy, 85 received CTx (49%); 70, ASCT (41%); 11, radiotherapy only (6%); and 4, palliative single agent therapies (2%). CTx was predominantly bleomycin, etoposide, doxorubicin cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP [68%]), followed by the combination regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (19%), or other regimens (13%). Patients aged > 60 years at relapse had shorter second PFS (hazard ratio [HR], 3.0; P = .0029) and were mostly treated with CTx (n = 33 of 49; 67%) and rarely with ASCT (n = 8; 16%). After adjustment for age and a disadvantage of ASCT after the more historic HD10 trial, we did not observe a significant difference in the efficacy of CTx versus ASCT for second PFS (HR, 0.7; 95% CI, 0.3 to 1.6; P = .39). In patients in the HD13 trial who were aged ≤ 60 years, the 2-year, second PFS rate was 94.0% with CTx (95% CI, 85.7% to 100%) versus 83.3% with ASCT (95% CI, 71.8% to 94.8%). Additional sensitivity analyses including OS confirmed these observations. CONCLUSION After contemporary treatment of ES-HL, relapse mostly occurred > 12 months after first diagnosis. Polychemotherapy regimens such as BEACOPP are frequently administered and may constitute a reasonable treatment option for selected patients with relapse after ES-HL.

Download Full-text

Adjuvant brachytherapy for FIGO stage I serous or clear cell endometrial cancer

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2020-002217 ◽

2021 ◽

pp. ijgc-2020-002217

Author(s):

Elizabeth B Jeans ◽

William G Breen ◽

Trey C Mullikin ◽

Brittany A Looker ◽

Andrea Mariani ◽

...

Keyword(s):

Endometrial Cancer ◽

Clear Cell ◽

Early Stage ◽

Figo Stage ◽

Stage I ◽

High Dose ◽

Vaginal Cuff ◽

Locoregional Failure ◽

Platinum Based Chemotherapy ◽

Increased Risk

ObjectivesOptimal adjuvant treatment for early-stage clear cell and serous endometrial cancer remains unclear. We report outcomes for women with surgically staged International Federation of Gynecology and Obstetrics (FIGO) stage I clear cell, serous, and mixed endometrial cancers following adjuvant vaginal cuff brachytherapy with or without chemotherapy.MethodsFrom April 1998 to January 2020, women with FIGO stage IA–IB clear cell, serous, and mixed endometrial cancer underwent surgery and adjuvant vaginal cuff brachytherapy. Seventy-six patients received chemotherapy. High-dose rate vaginal cuff brachytherapy was planned to a total dose of 21 gray in three fractions using a multichannel vaginal cylinder. The primary objective was to determine the effectiveness of adjuvant vaginal cuff brachytherapy and to identify surgicopathological risk factors that could portend towards worse oncological outcomes.ResultsA total of 182 patients were included in the analysis. Median follow-up was 5.3 years (2.3–12.2). Ten-year survival was 73.3%. Five-year cumulative incidence (CI) of vaginal, pelvic, and para-aortic relapse was 1.4%, 2.1%, and 0.9%, respectively. Five-year locoregional failure, any recurrence, peritoneal relapse, and other distant recurrence was 4.4%, 11.6%, 5.3%, and 6.7%, respectively. On univariate analysis, locoregional failure was worse for larger tumors (per 1 cm) (HR 1.9, 95% CI 1.2 to 3.0, p≤0.01). Any recurrence was worse for tumors of at least 3.5 cm (HR 3.8, 95% CI 1.3 to 11.7, p=0.02) and patients with positive/suspicious cytology (HR 4.4, 95% CI 1.5 to 12.4, p≤0.01). Ten-year survival for tumors of at least 3.5 cm was 56.9% versus 86.6% for those with smaller tumors (HR 2.9, 95% CI 1.4 to 5.8, p≤0.01). Ten-year survival for positive/suspicious cytology was 50.9% versus 77.4% (HR 2.2, 95% CI 0.9 to 5.4, p=0.09). Multivariate modeling demonstrated worse locoregional failure, any recurrence, and survival with larger tumors, as well as any recurrence with positive/suspicious cytology. Subgroup analysis demonstrated improved outcomes with the use of adjuvant chemotherapy in patients with large tumors or positive/suspicious cytology.ConclusionAdjuvant vaginal cuff brachytherapy alone without chemotherapy is an appropriate treatment for women with negative peritoneal cytology and small, early-stage clear cell, serous, and mixed endometrial cancer. Larger tumors or positive/suspicious cytology are at increased risk for relapse and worse survival, and should be considered for additional upfront adjuvant treatments, such as platinum-based chemotherapy.

Download Full-text

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

Scientific Reports ◽

10.1038/s41598-021-93232-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daekwon Bae ◽

Ji-Young Lee ◽

Nina Ha ◽

Jinsol Park ◽

Jiyeon Baek ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Immune Responses ◽

Therapeutic Potential ◽

Autoimmune Encephalitis ◽

Selective Inhibitor ◽

Therapeutic Effects ◽

Treatment Regimens ◽

Ifn Γ ◽

Experimental Autoimmune

AbstractDespite 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.

Download Full-text