Central Nervous System Regulation of Inflammation
A theme of Dr. Firestein’s work over the last several years has been the investigation of how the mitogen-activated protein (MAP) kinases affect the development and maintenance of rheumatoid inflammation. The work currently funded by the Arthritis Foundation focuses on one such MAP kinase, known as p38.
What Problem Was Studied?
p38 MAP kinase is likely involved in several cell processes critical to the development of rheumatoid arthritis (RA). Substances that block the action of p38 are being tested as treatment for RA. When given systemically, however, these medications have often caused side effects.
Previous studies have indicated that the central nervous system (CNS) can potentially regulate immune function and inflammation in peripheral tissue. Furthermore, p38 is activated in the CNS in response to pain. Armed with this knowledge, Firestein and colleagues ran a series of tests to determine whether and how p38 within the central nervous system regulates inflammation in a rat model of rheumatoid arthritis.
What Was Done in the Study?
Rats with adjuvant arthritis had small tubes inserted directly into their spinal canals (intrathecal catheters) through which medications could be dispensed. A chemical that blocks p38 was administered through the catheters of one group of rats and saline was used as a control in a different group of rats. The inhibitor was also given to a group of rats via an injection under the skin (subcutaneous). Various arthritis and inflammation parameters were measured. Cytokine gene expression, T cell proliferation and p38 activation were also studied to determine the mechanisms of action of p38 within the CNS.
What Were the Study Results?
Intrathecal administration of a p38 inhibitor markedly reduced paw swelling and radiographic evidence of joint damage in rats with adjuvant arthritis compared with rats treated with intrathecal saline or the same dose of inhibitor administered subcutaneously. The intrathecally dispensed inhibitor significantly decreased proinflammatory cytokines within the synovium, but had no effect on T-cell proliferation. Firestein concluded in his article that “blockade of p38 has profound effects on peripheral inflammation, arthritis, proinflammatory gene expression, and joint destruction.”
Because the proinflammatory cytokine tumor necrosis factor α (TNF-α) and p38 can participate in the same signaling cascade, the team also ran experiments using etanercept (an inhibitor of TNF-α). When etanercept was administered through the intrathecal catheter, paw swelling and joint destruction were significantly decreased, but systemic treatment with the same dosage had minimal effect. This striking result suggests that TNF-α in the CNS can contribute to synovial inflammation.
What Do These Results Mean to People with RA?
Systemic p38 inhibition has been extensively studied and clearly demonstrates benefit in animal models of arthritis. However, doses several hundred-fold higher than the amount needed for intrathecal therapy are usually required with oral or parenteral routes. Firestein raises the possibility that the “CNS might be responsible for the anti-inflammatory effects seen with systemic administration,” but that p38 inhibitors with inadequate CNS penetration might have limited efficacy. He suggests that compounds that can penetrate the blood-brain barrier could be developed that would maximize anti-inflammatory action and enhance pain-relieving effects.