Secondary Topic: Basic Science
Tertiary Topic: Research Methodology
The translational potential of celastrol, a natural triterpenoid, for arthritis therapy
Steven Dudics, B.S., , Baltimore, MD, United States; Rakeshchandra R Meka, M.S.; Shivaprasad H Venkatesha, PhD, University of Maryland School of Medicine, Baltimore, MD, United States; Chun-Tao Che, PhD, College of Pharmacy, University of Illinois, Chicago, IL, United States; Brian M Berman, M.D.; Kamal D. Moudgil, MD, PhD, University of Maryland School of Medicine, Baltimore, MD, United States
Late Breaker: No
Rheumatoid arthritis (RA) is a multifactorial disease that involves both genetic and environmental components. Approximately 1% of the world’s population is afflicted with RA. Current treatments, including biologics such as anti-TNFα, are effective, but only in about 50-60% of RA patients. In addition, the use of biologics may render some RA patients vulnerable to infections. Therefore, there is an urgent need to identify and develop new therapeutic agents for RA. We tested celastrol, a triterpenoid derived from the traditional Chinese herb Celastrus aculeatus Merr, which possesses anti-inflammatory properties.
Celastrol was administered to arthritic rats intraperitoneally (i.p.) (1mg/Kg) daily until the experimental end point. This treatment suppressed arthritis progression. However, i.p. route of injection of celastrol is limiting in its practical use in humans. Therefore, in subsequent experiments, we tested the effects of orally-administered celastrol (5mg/kg) on arthritis in rats. The treatment was begun at the onset of arthritis and continued through the peak phase of the disease. Arthritis severity was assessed clinically and histologically, the lymphoid cells were tested for cytokines, and the sera were tested for antibodies.
We observed a significant reduction in arthritic scores compared to controls. Moreover, key pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and IL-17 were decreased along with reduction in the T cell response and antibodies to antigens relevant for disease pathogenesis. Also assessed was the effect of celastrol on the relative frequency of T helper 17 and T regulatory cells in the draining lymphoid cells, and it was found to favor immune regulation.
Our results demonstrate that celastrol administered via the oral route had beneficial anti-arthritic effect, as was also observed with intraperitoneal delivery. The added benefit to oral delivery is its translational capabilities, which will allow this work to eventually move from the bench to treating patients.