VBP15, a Novel Anti-Inflammatory, is Effective at Reducing the Severity of Murine Experimental Autoimmune Encephalomyelitis

Abstract

Multiple sclerosis is a chronic disease of the central nervous system characterized by an autoimmune inflammatory reaction that leads to axonal demyelination and tissue damage. Glucocorticoids, such as prednisolone, are effective in the treatment of multiple sclerosis in large part due to their ability to inhibit pro-inflammatory pathways (e.g., NFκB). However, despite their effectiveness, long-term treatment is limited by adverse side effects. VBP15 is a recently described compound synthesized based on the lazeroid steroidal backbone that shows activity in acute and chronic inflammatory conditions, yet displays a much-reduced side effect profile compared to traditional glucocorticoids. The purpose of this study was to determine the effectiveness of VBP15 in inhibiting inflammation and disease progression in experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of multiple sclerosis. Our data show that VBP15 is effective at reducing both disease onset and severity. In parallel studies, we observed that VBP15 was able to inhibit the production of NFκB-regulated pro-inflammatory transcripts in human macrophages. Furthermore, treatment with prednisolone-but not VBP15-increased expression of genes associated with bone loss and muscle atrophy, suggesting lack of side effects of VBP15. These findings suggest that VBP15 may represent a potentially safer alternative to traditional glucocorticoids in the treatment of multiple sclerosis and other inflammatory diseases.

OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages

“…The transcripts included in the custom Nanostring panel were chosen based on previous microarray data demonstrating the acute upregulation of these transcripts in response to pro‐inflammatory and pro‐fibrotic stimuli and have been published elsewhere (Dillingham et al . 2015). OPN‐a induced the greatest amount of pro‐inflammatory transcript induction (Fig.…”

“…2015). Briefly, cells were harvested in cell stripper (Cellgro, Manassas, VA, USA), washed and resuspended in RLT Buffer (Qiagen, Hilden, Germany).…”

VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis

“…VBP15 is an anti-inflammatory compound that has been shown to be an effective inhibitor of NFjB activity both in vitro and in vivo [19][20][21][22] but does not induce the GREmediated transcription (genomic transactivation property) believed to be responsible for many of the detrimental metabolic side effects of glucocorticoids [19,21]. In the current study, VBP15 inhibited the production of pro-inflammatory cytokines IL-6 and IL-8, as well as chemokine, CCL5, in TNFa-stimulated human intestinal epithelial cells.…”

“…Having previously shown that VBP15 reduces NFjB activity in vitro in muscle cells, lung cells, splenocytes, and macrophages [19][20][21][22], we sought to determine if VBP15 could reduce the expression of pro-inflammatory NFjBregulated cytokines in human intestinal epithelial cells. We treated intestinal epithelial cells for 24 h with VBP15 (10 lM), prednisolone (10 lM), or vehicle control (DMSO) and subsequently stimulated them with TNFa for an additional 24 h. Focusing on three cytokines (CCL5, IL-6 and IL-8) that are important in the pathogenesis of IBD, we found that VBP15 treatment significantly reduced the expression of all three by at least 68 %, and to a similar degree to that observed with prednisolone (Fig.…”

“…1). VBP15 has demonstrated strong anti-inflammatory activity in vivo across multiple murine models of disease, while resulting in a reduced glucocorticoid-associated side effect profile [20][21][22]. The purpose of this study was to assess the effect of VBP15 on disease symptoms in the TNBS-induced mouse model of colitis and further characterize VBP15's in vivo effects on growth during chronic treatment in juvenile mice.…”