Effective treatment of rat adjuvant-induced arthritis by celastrol

Abstract

We have previously reported an increase in interleukin (IL)-1β and IL-17 levels, and a continuous activation of caspase-1 in early rheumatoid arthritis (RA) patients. These results suggest that drugs targeting IL-1β regulatory pathways, in addition to tumor necrosis factor (TNF), may constitute promising therapeutic agents in early RA. We have recently used a THP-1 macrophage-like cell line to screen 2320 compounds for those that down-regulate both IL-1β and TNF secretion. Celastrol was one of the most promising therapeutic candidates identified in that study. Our main goal in the present work was to investigate whether administration of celastrol is able to attenuate inflammation in a rat model of adjuvant-induced arthritis (AIA). Moreover, since IL-1β is known to play a role in the polarization of Th17 cells, we also investigate whether administration of digoxin, a specific inhibitor of Th17 cells polarization, is able to attenuate inflammation in the same rat model. We found that celastrol administration significantly suppressed joint inflammation. The histological and immunohistochemical evaluation revealed that celastrol-treated rats had a normal joint structure with complete abrogation of the inflammatory infiltrate and cellular proliferation. In contrast, we observed that digoxin administration significantly ameliorated inflammation but only if administrated in the early phase of disease course (after 4 days of disease induction), and it was not efficient at inhibiting the infiltration of immune cells within the joint and in preventing damage. Thus, our results suggest that celastrol has significant anti-inflammatory and anti-proliferative properties and can constitute a potential anti-inflammatory drug with therapeutic efficacy in the treatment of immune-mediated inflammatory diseases such as RA. Furthermore, we find that early inhibition of Th17 cells polarization ameliorates arthritis but it is not as effective as celastrol.

Modulatory effect of celastrol on Th1/Th2 cytokines profile, TLR2 and CD3+ T-lymphocyte expression in a relapsing–remitting model of multiple sclerosis in rats

“…Treatment of rats in group III with celastrol (was prepared as 1 mg/ml solution in 1% DMSO) in a dose of 1 mg/kg/ day given by intraperitoneal (i.p.) injection (Cascão et al, 2012) was started at the 10th day post-immunization (p.i.) and continued till the end of the experiment at the 42nd day.…”

Pristimerin, a naturally occurring triterpenoid, protects against autoimmune arthritis by modulating the cellular and soluble immune mediators of inflammation and tissue damage

“…and other sources (e.g., Boswellia extract, Boswellic acids, green tea polyphenolic extract, epigallocatechin gallate (EGCG), etc.) that have been, or are being, explored as therapeutic agents for experimental arthritis and human RA [21,30,[51][52][53][54][55][56][57]. Pristimerin needs to be tested further for its additive or synergistic effects with other naturally occurring bioactive compounds as well as with conventionally used mainstream anti-arthritic drugs (e.g., non-steroidal anti-arthritic drugs (NSAIDs), diseasemodifying anti-rheumatic drugs (DMARDs), etc.).…”

Th17 cells in autoimmune diseases

“…Based on a small molecule screen, several RORγt inhibitors are identified, including digoxin, ML209, SR1001, SR2211, and ursolic acid [108]. Treating animals with these small molecules not only delays the onset but also alleviates the severity of models of EAE and CIA [109][110][111][112]. Recently, TMP778, TM920, and GSK805, which were screened from a benzhydryl amide group, have been identified as highly potent and selective RORγt inhibitors [113].…”