The central nervous system is not just a passive responder to the outside world, but is fully able to control many previously unanticipated 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 UCSD research team found that blocking key signaling enzymes in the CNS of rats resulted in decreased joint inflammation and destruction. Their findings will be published in the September edition of the journal Public Library of Science (PLoS) Medicine.
"This is an entirely new approach," Firestein said. ¡§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."
For many years, researchers have explored developing therapeutic targets by blocking the function of a signaling enzyme called p38 MAP kinase throughout the body. This enzyme regulates cytokines proteins released in response to stress that regulate inflammation in patients with arthritis. p38 is known to regulate production of a one particular cytokine called TNFƒÑ, and inhibitors of this cytokine are effective therapies for rheumatoid arthritis. Typically, researchers attempt to inhibit proteins in the main tissues affected by the disease, such as the joints in arthritis or the colon in inflammatory bowel disease.
UCSD's multidisciplinary research team including Linda Sorkin, Ph.D., Department of Anesthesiology and David L. Boyle, Department of Medicine thought that the CNS 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 used a novel drug delivery system to administer miniscule amounts of a compound that blocks these signals only in the CNS and then determined the influence of the treatment on peripheral arthritis.
We observed that the p38 signal is turned on, or activated, in the central nervous system during peripheral inflammation," Firestein said. "If we blocked this enzyme exclusively in a highly restricted site but not throughout in 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 TNFƒÑ might also play a role in this observation. Using a TNF-inhibitor that is approved for use in rheumatoid arthritis and is usually given throughout the body, 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 implications 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.
Debra Kain | EurekAlert!
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