Isolated Compound from Chinese Herb Proven to Work in Collagen-Induced Arthritis

What problem was studied?
There has been a great demand for new antirheumatic agents that are able to act on chemical mediators of inflammation, but have fewer toxic effects and cost less than the current treatments that block the actions of tumor necrosis factor α and interleukin-1. Practitioners of traditional Chinese medicine have been using the medicinal plant Tylophora atrofolliculata to treat rheumatism for a thousand years; the herb is not readily available in the United States, however. Researchers from Yale University and University of Tennessee, Knoxville, have isolated an active compound from the Tylophora plant and have been studying its effects on collagen-induced arthritis, a well-studied animal model of rheumatoid arthritis (RA).

What was done in the study?
Several extracts have been isolated and synthesized from the Tylophora plant. One such analog, DCB 3503, was previously shown to inhibit the actions of a chemical known to be involved in tumor growth and inflammation. This analog was therefore chosen to be used in this experiment.

Arthritis Foundation-funded researcher Zhinan Yin, MD, and colleagues injected mice with bovine collagen. In this particular strain of mice, such an injection is known to induce inflammatory arthritis that mimics RA. After 21 days, the mice were given a booster injection of bovine collagen. Thereafter, mice were monitored daily for signs of arthritis. Arthritis severity was graded on a scale of 0-3.

The injection of lipopolysaccharide (LPS) is known to accelerate the development of collagen-induced arthritis. On day 28 after the initial collagen immunization, some of the mice were injected with LPS.

To test the effects of DCB 3503 on collagen-induced arthritis, mice were treated with either the analog or a control chemical at different time points after collagen immunization. Mice were treated either before the onset of inflammation or after the onset of inflammation. To test the effects of DCB 3503 on the LPS-enhanced arthritis model, a portion of the collagen-injected mice were treated with the DCB 3503 either before or after the injection of LPS.

What were the study results?
Mice treated with DCB 3503 before the onset of inflammation showed decreased severity and delayed onset of arthritis. Only 1 of 8 mice in the active treatment group developed mild arthritis, but 9 of 10 mice in the control group developed arthritis. Once DCB 3503 therapy was discontinued, the incidence and severity of arthritis increased in the treatment group.

Mice treated with DCB 3503 after the onset of inflammation showed no progression or even a reduced severity of arthritis. The control mice, however, continued to develop severe arthritis.

Some of the mice were injected with LPS to accelerate the development of arthritis. Mice treated with DCB 3503 before the LPS injection remained free of arthritis. However, the control group (which received LPS but not DCB 3503) developed severe arthritis. Likewise, progression of arthritis in mice treated with DCB 3503 after the LPS injection was halted.

Microscopic views of the affected joints further showed that the degree of joint destruction was reduced in treated animals. Additional laboratory tests showed that DCB 3503 had little effect on the initiation of inflammatory joint disease, but rather worked on events in the chemical cascade that are important for the continuation and dissemination of inflammatory joint disease.

What’s the relevance to people with arthritis?
This study demonstrates that DCB 3503, a tylophorine analog derived from the Tylophora plant, effectively inhibits the development and progression of collagen-induced arthritis in mice. It has been shown to do this by suppressing the production of proinflammatory chemicals and mediators of inflammation. These results suggest that DCB 3503 has potential as a therapeutic agent for inflammatory arthritis in humans.

The next step toward the development of such a therapeutic agent is a clinical trial. Researchers at Yale are now seeking the funding to begin such a trial.

Source: Arthritis & Rheumatism, Vol. 54, No. 3
http://www3.interscience.wiley.com/cgi-bin/abstract/112468467/ABSTRACT

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