The painful inflammation and debilitating joint damage characteristic of rheumatoid arthritis may be reduced or prevented with a new approach using small-molecule enzyme mimetics, according to research published in the journal Arthritis & Rheumatism.
The preclinical study conducted by researchers at MetaPhore Pharmaceuticals, Inc.® and the University of Messina, Italy showed that a superoxide dismutase (SOD) mimetic, substantially reduced the erosion of cartilage and bone, and the chronic inflammation of rheumatoid arthritis in a standard animal model.
The SOD mimetic was also shown to markedly reduce elevated levels of two pro-inflammatory cytokines (immune regulating substances produced by immune cells). These are tumor necrosis factor alpha (TNF-á) and interleukin-1â (IL-1â), which are intricately involved in the development of arthritis in humans.
As part of the body’s oxidative chemistry, SOD enzymes regulate normal levels of superoxide. Certain disease states like rheumatoid arthritis, however, promote an overproduction of superoxide and the natural enzymes are overwhelmed. For example, excessive amounts of superoxide have been shown to contribute to inflammatory processes, inhibit certain disease fighting mechanisms, and affect mechanisms involved in regulating vascular pressure.
Rheumatoid arthritis, the most common chronic inflammatory disease, is an autoimmune disease, where elements of the body’s immune system attack specific points in the body itself, such as the joints. These pro-inflammatory immune response factors include TNF-á, IL-1â, and superoxide, a free radical that, in excess, is a significant mediator of tissue and cell damage and regulates cytokine release.
To determine the potential of selective removal of superoxide in treating rheumatoid arthritis, researchers tested the SOD mimetic M40403. This mimetic is a small-molecule SOD mimetic designed to replicate the action of natural SOD enzymes, and selectively remove excess superoxide.
SOD mimetics are promising drug candidates because they have a low molecular weight, are highly stable and do not appear to elicit an immune response in the body. Furthermore, the chemical structure of the metal-based compounds can be easily optimized for application to different diseases and conditions.
In the study, researchers evaluated the effects of daily doses of M40403 on the development and progression of arthritis in rats. In animals treated with M40403 results showed inflammation was reduced by up to 56%, joint erosion was reduced by at least 70%, and TNF-a and IL-1b levels were reduced, at two of the doses tested, to those typical of normal, non-arthritic rats.
“The findings of this study suggest a potentially novel therapeutic for rheumatoid arthritis, combining anti-inflammatory and disease-modifying properties into a single drug,” said Daniela Salvemini, Ph.D., MetaPhore’s Vice President of Pharmacology and the principal investigator. “The SOD mimetic possesses both of these properties because superoxide plays a dual role, in acting both as a direct inflammatory molecule as well as stimulating the release of the inflammatory cytokines, TNF-á and IL-1â. This contrasts with the current generation of disease-modifying arthritis drugs which attempt to control the cytokines after their release.”
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