A New Orally Bioavailable Synthetic Androstene Inhibits Collagen‐Induced Arthritis in the Mouse

Abstract

Dehydroepiandrosterone (DHEA) has attracted much interest because of its many antiaging, metabolic and immune-modulating effects in rodents. Synthetic derivatives, such as 5-androstene-16alpha-fluoro-17-one (HE2500) and certain natural metabolites also provide benefit in various animal models of autoimmune and metabolic diseases. But, like DHEA, low potency and low oral bioavailability suggested limited usefulness of these compounds in humans. We hypothesized that HE3286, a novel 17-ethynyl derivative would be orally bioavailable, more potent, and chemically more useful in man than its parent compound. We found that on a dose/mass basis, HE3286 demonstrated up to 25% oral bioavailability in mice. In the DBA mouse model of collagen-induced arthritis (CIA), animals receiving oral treatment with HE3286 (50 mg/kg), beginning at onset of disease, significantly decreased CIA peak scores and daily severity of arthritis scores. Benefit was associated with decreases in: (1) production of TNF-alpha, IL-6, and IL-17; and (2) decreases in joint inflammation, erosion, and synovial proliferation as judged by histological analysis. HE3286 was not found to be immune suppressive in any of the classical models tested, including mitogen-induced proliferation, delayed-type hypersensitivity, or mixed lymphocyte reaction. Instead, benefit was associated with increases in numbers and function of CD4+CD25+FOXp3+CD127- regulatory T cells (T reg). To our knowledge, this is probably the first study to report that an orally bioavailable synthetic analogue of DHEA can ameliorate ongoing disease in a CIA mouse model with relevance to rheumatoid arthritis (RA) and to correlate that finding with decreases in proinflammatory cytokines and increases in T reg cells. Hormones targeting T reg cells hold the intriguing potential to treat autoimmune, infectious, and neoplastic diseases.

An Orally Bioavailable Synthetic Analog of an Active Dehydroepiandrosterone Metabolite Reduces Established Disease in Rodent Models of Rheumatoid Arthritis

“…Treatment was associated with reductions in activated NF-B, proinflammatory cytokines mRNAs, and MMP-3. Across multiple studies, including those reported here and previously (Auci et al, 2007), we hypothesize a mechanism based on reduced NF-B activation and increased regulatory T-cell levels.…”

“…In our previous studies, we found that when treatment with HE3286 began at disease onset, within 13 days of treatment, HE3286-treated mice displayed a significant (p Ͻ 0.04) decrease in CIA score compared with animals treated with vehicle alone from approximately 13 days after onset to approximately 18 days after onset (Auci et al, 2007).…”

“…Because of the pathological similarities between CIA and RA, the CIA model has been the subject of extensive investigation and is a common model in which many putative antiarthritic agents are tested. In our previous studies, we reported that HE3286-treated mice displayed a significant decrease in CIA disease score and increased regulatory T cells compared with animals treated with vehicle alone (Auci et al, 2007). In the collagen antibody-induced arthritis (CAIA) model, the typical disease course involves a short period of acute disease followed by gradual resolution in joint inflammation (Nandakumar et al, 2003).…”

Dynamic Frequency of Blood CD4+CD25+ Regulatory T Cells in Rats with Collagen-induced Arthritis

“…We also found that the mRNA and protein level of Foxp3 was decreased in the spleens of CIA rats than in normal controls and could be improved by leflunomide both in vivo and in vitro [23]. These results are consistent with our hypothesis of the involvement of CD4+CD25+Tregs in CIA progression and with the findings of several published studies, which showed an increase of CD4+CD25+Tregs in the therapeutic effect of anti-arthritic drugs on CIA [24][25][26][27].…”

Oral treatment with HE3286 ameliorates disease in rodent models of rheumatoid arthritis

“…We previously reported that oral treatment with HE3286 inhibited collagen-induced arthritis in the mouse (27,28). To extend and complement this finding we evaluated the effect of HE3286 in the Lewis rat model of adjuvant-induced arthritis (AIA) that represents another well known and validated preclinical model of human RA (29).…”