Rheumatoid arthritis drugs work better, at least in arthritic rats, when delivered into the central nervous system, Gary Firestein and colleagues (University of California San Diego) now report in the international open-access medical journal PLoS Medicine.
Rheumatoid arthritis (RA) is a disease marked by chronic inflammation, leading to joint pain and destruction. Pain and inflammation in the joints are constantly monitored by the central nervous system (CNS, i.e. the brain and spinal cord). Scientists have long suspected that the CNS can regulate inflammation and immune responses in the body's "periphery", but little is known about how this works. Firestein and colleagues focused on a protein called p38, which is involved in a number of cellular processes critical to the development of RA. Several substances that block the action of p38 are effective in animal models of arthritis and are currently being tested in clinical trials in patients with RA.
Based on the observation by other scientists that p38 is activated in the CNS in response to peripheral pain, and on Firestein and colleagues' own finding that this is true in response to inflammation as well, the researchers blocked p38 with drugs directly delivered to the spinal cord of the arthritic rats. They found that the treated rats had substantially less inflammation, arthritis, and joint destruction, compared with rats that had undergone the same treatment but received no active drug. Treatment of arthritic rats with the same amount of drugs given directly under the skin (the "systemic treatment" that is currently being tested in RA patients, but with much higher doses) did not have any beneficial effect on the joints.
These findings suggest that spinal cord administration might reduce the side effects (and possibly the costs) of p38 inhibitors without compromising the benefits to patients. And if future studies confirm that the action of these drugs on the CNS is essential to achieve a response even when administered as a systemic treatment, designing drugs that get into the CNS easier might improve the effectiveness and/or make it possible to use lower doses systemically.
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Citation: Boyle DL, Jones TL, Hammaker D, Svensson CI, Rosengren S, et al. (2006) Regulation of peripheral inflammation by spinal p38 MAP kinase in rats. PLoS Med 3(9): e338. DOI: 10.1371/journal.pmed.0030338.
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