Looking for a way to cure arthritis? Try your brain!
by Nathan Wei, MD
The major event that initiates and perpetuates arthritis is inflammation. Theories abound as to how inflammation both starts as well as continues. A recent study has indicated that inflammation in the joints can be sensed and modulated by the central nervous system (CNS). The research suggests that the CNS can influence the immune response. It is possible this effect may explain both the so-called pl
acebo effect as well as the role of stress in inflammatory diseases.
For years, researchers have developed therapeutic targets by blocking the function of various protein messengers called cytokines. Cytokine function is regulated by various enzymes throughout the body. One of these signaling enzymes is called p38 MAP kinase.
This enzyme regulates cytokine proteins released in response to stress. These cytokines, in turn, regulate inflammation in patients with arthritis. The enzyme, p38, is known to regulate production of a one particular cytokine called tumor necrosis factor (TNF). Inhibitors of TNF are effective therapies for rheumatoid arthritis. Examples include Enbrel, Humira, and Remicade.
Typically, researchers attempt to inhibit proteins in the target organ such as the joints in arthritis.
Researchers at the University of California at San Diego's School of Medicine have postulated an interesting theory that the central nervous system (CNS) - the brain might play a more important role in controlling the symptoms of rheumatoid arthritis than previously believed.
To test their hypothesis, the researchers studied the p38 MAP kinase signaling in rat spinal cords.
The scientists administered tiny amounts of a compound that blocks these signals only in the CNS and then determined the influence of the treatment on peripheral arthritis.
"The central nervous system is not just a passive responder to the outside world, but is fully able to control many... physiologic responses, including immunity and inflammation," said Gary S. Firestein, M.D., Professor of Medicine, Chief of the Division of Rheumatology, Allergy and Immunology, and Director of UCSD's Clinical Investigation Institute, who led the study.
The researchers found that blocking key signaling enzymes in the CNS of rats resulted in decreased joint inflammation and destruction. Their findings will be published soon in the journal Public Library of Science (PLoS) Medicine.
"Instead of targeting enzymes at the actual site of disease, our hypothesis is that the central nervous system is a controlling influence for the body and can regulate peripheral inflammation and immune responses, Firestein added."
We observed that the p38 signal is activated in the central nervous system during peripheral inflammation," Firestein said. "If we blocked this enzyme exclusively in the CNS but not throughout the body, inflammation in the joints was significantly suppressed."
Not only were clinical signs of arthritis diminished in those rats where p38 inhibitors were administered into the spinal fluid, but damage to the joint was also markedly decreased. The same dose of the inhibitors administered systemically had no effect.
The group also explored whether TNF might also play a role. Using a TNF-inhibitor that is approved for use in rheumatoid arthritis, the scientists showed that delivering small amounts of this agent into the central nervous system also suppressed arthritis and joint destruction in the rats.
They proposed that inflammation in the joints increases TNF production in the central nervous system, which, in turn, activates spinal p38. By blocking this pathway only in the spinal cord, they observed the same benefit that was normally achieved by treating the entire body with much higher doses.
The novel mechanism could have therapeutic impact related to the design and delivery of anti-inflammatory drugs, and may be related to the way pain signals are perceived by the brain. The study also shows that the interactions between the CNS and the body are highly complex.
Additional contributors include Deepa Hammaker, Sanna Rosengren and Salvatore Albani, UCSD Division of Rheumatology, Allergy and Immunity; and Toni L. Jones and Camille I. Svensson, UCSD Department of Anesthesiology. The research was supported by grants from the Arthritis Foundation and the National Institute of Arthritis and Musculoskeletal and Skin Disease.
Authors note: This study is fascinating. We know that the placebo response in arthritis clinical trials may be as high as 40%. Studies like this one may help elucidate the mechanism of how placebo works. The ability to harness the curative effects of the brain is very promising.
Note: This story has been adapted from a news release issued by University of California - San Diego and Science Daily (http://www.sciencedaily.com)
About the Author
Nathan Wei, MD, FACP, FACR is a rheumatologist and Director of the Arthritis and Osteoporosis Center of Maryland (http://www.aocm.org). He is a Clinical Assistant Professor of Medicine at the University of Maryland School of Medicine and consultant to the National Institutes of Health. For more info: {a href=" http://www.arthritis-treatment-and-relief.com/arthritis-treatment.html"}Arthritis Treatment