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

Offner, Halina; Firestein, Gary S.; Boyle, David L.; Pieters, Raymond; Frincke, James M.; Garsd, Armando; White, Steven K; Reading, Christopher L.; Auci, Dominick L.

doi:10.1124/jpet.108.145086

Cited by 25 publications

(30 citation statements)

References 35 publications

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“…This resembles our present observation of concomitant inhibition of clinical signs of AIA and reduced blood levels of IL-6 (and TNF-·) in the rats treated with HE3286. These findings are also consistent with our studies in murine type II CIA where HE3286-mediated clinical benefit was associated with decreased production of pro-inflammatory cytokines such as TNF-·, IL-6, and IL-17 (28). The above findings may indicate that the anti-arthritogenic capacities of HE3286 may be at least partly mediated by its capacity to down-regulate the synthesis of proinflammatory cytokines involved in arthritogenic pathways such as IL-6 and TNF-·.…”

Section: Discussionsupporting

confidence: 82%

“…Our observation that HE3286 provides benefit in the rat model of AIA, even when treatment is delayed until disease is well established, is in agreement with our previous studies in the type II CIA DBA mouse model of arthritis (28). This observation has strong significance for the potential translation of these findings to the clinical setting as it has been shown that a compound's therapeutic efficacy, rather than prophylactic efficacy, in AIA and CIA models is more predictive of clinical efficacy in human RA than data from either model alone (29).…”

Section: Discussionsupporting

confidence: 81%

“…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). We also replicated and confirmed the previously observed effects of HE3286 in the DBA mouse model of collagen antibodyinduced arthritis (CAIA) (28). In addition, we demonstrated that HE3286 is devoid of immunosuppressive properties both in in vitro and in vivo experimental settings using the mixed lymphocyte reaction response and the murine model of Coxsackie B3 virus-induced myocarditis, respectively.…”

Section: Introductionsupporting

confidence: 62%

“…To induce arthritis, mice were administered 1 mg of an anti-bCII antibody cocktail (Chondrex, Redmond, WA) intravenously on day -2. On day 0, animals were treated intraperitoneally (IP) with LPS (12.5 μg), as in a previous study (28). The arthritic severity of the mice was evaluated as in our AIA studies.…”

Section: Collagen Antibody Induced Arthritis (Caia)mentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Nicoletti¹

2010

Int J Mol Med

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Abstract. 7ß, is an orally bio-available synthetic derivative of naturally occurring androstene-3ß, 7ß, 17ß-triol. Our present data show that oral treatment with HE3286, favourably influenced the course of arthritis in the rat model of adjuvant-induced arthritis (reduced cumulative disease scores and paw edema), and in the mouse model of collagen antibody-induced arthritis (reduced clinical paw scores). Importantly, HE3286 was not immune suppressive in human mixed lymphocyte reaction or in animals challenged with Coxsackie B3 virus. HE3286 is currently in phase I/II clinical trials in rheumatoid arthritis and ulcerative colitis and these findings further strengthen the possibility that HE3286 may represent an effective antiinflammatory agent useful for treating chronic inflammation with a more attractive safety profile than glucocorticoids or cyclooxygenase inhibitors.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 81%

Section: Introductionsupporting

confidence: 62%

Section: Collagen Antibody Induced Arthritis (Caia)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Nicoletti¹

2010

Int J Mol Med

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A synthetic anti‐inflammatory sterol improves insulin sensitivity in insulin‐resistant obese impaired glucose tolerance subjects

Reading¹,

Stickney²,

Flores-Riveros³

et al. 2013

Obesity

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Objective: To study the activity of 7b,, an antiinflammatory sterol that is active in models of obesity-induced inflammation and insulin resistance in high body mass index (BMI) subjects with impaired glucose tolerance (IGT). Design and Methods: HE3286 was explored in high BMI IGT subjects using hyperinsulinemic, euglycemic clamp studies. Results: In insulin-resistant subjects, HE3286 significantly increased day 29 insulin-stimulated glucose disposal and HDL cholesterol, and decreased C-reactive protein (CRP) compared to placebo. For HE3286, change in M value showed a significant negative correlation with baseline M value. Subjects with baseline M value below the median (4.2 mg/kg/min) had significantly lower adiponectin and higher lipopolysaccharide-stimulated peripheral blood mononuclear cell cytokine secretion. After 28 days of HE3286 treatment, adiponectin levels were significantly increased in insulin-resistant (baseline M < 4.2), but not insulin-sensitive (baseline M > 4.2) subjects, compared to placebo. Conclusions: HE3286 significantly increased the frequency of subjects with increased insulin-stimulated glucose disposal and HDL, and decreased CRP compared to placebo, in insulin-resistant, but not insulin-sensitive subjects. Thus, HE3286 may preferentially benefit insulin-resistant, inflamed, high BMI IGT subjects.

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Dehydroepiandrosterone Suppresses Eosinophil Infiltration and Airway Hyperresponsiveness via Modulation of Chemokines and Th2 Cytokines in Ovalbumin-Sensitized Mice

Liou¹,

Huang²

2011

J Clin Immunol

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In this study, we evaluated the anti-inflammatory response and the mechanism by which dehydroepiandrosterone modulates immunity in ovalbumin-sensitized asthmatic mice. Female BALB/c mice were sensitized and challenged with ovalbumin and then treated with oral administration of dehydroepiandrosterone on days 21 to 27. The results showed dehydroepiandrosterone could suppress airway hyperresponsiveness and decrease eosinophil infiltration of the lungs in ovalbumin-sensitized mice. Moreover, dehydroepiandrosterone inhibited chemokines, including CCL11/eotaxin-1 and CCL24/eotaxin-2, and Th2-associated cytokine levels in bronchoalveolar lavage fluid. After the inflammatory human bronchial epithelial cell line BEAS-2B was treated with dehydroepiandrosterone, levels of proinflammatory cytokines and chemokines were inhibited, including IL-6, IL-8, CCL11, and CCL24. We suggested that dehydroepiandrosterone inhibited inflammation in bronchial epithelial cells as indicated by the suppression of Th2-associated cytokines and chemokines. Dehydroepiandrosterone also suppressed eosinophil migration and infiltration into the lung to improve the symptoms of asthma in ovalbumin-sensitized mice.

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

Cited by 25 publications

References 35 publications

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

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

A synthetic anti‐inflammatory sterol improves insulin sensitivity in insulin‐resistant obese impaired glucose tolerance subjects

Dehydroepiandrosterone Suppresses Eosinophil Infiltration and Airway Hyperresponsiveness via Modulation of Chemokines and Th2 Cytokines in Ovalbumin-Sensitized Mice

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