a-MSH Modulates Local and Circulating Tumor Necrosis Factor-a in Experimental Brain Inflammation

Tumor necrosis factor (TNF-a) underlies pathological processes and functional disturbances in acute and chronic neurological disease and injury. The neuroimmunomodulatory peptide a-MSH modulates actions and production of proinflammatory cytokines including TNF-a, but there is no prior evidence that it alters TNF-a induced within the brain. To test for this potential influence of the peptide, TNF-a was induced centrally by local injection of bacterial lipopolysaccharide (LPS). a-MSH given once i.c.v. with LPS challenge, twice daily intraperitoneally (i.p.) for 5 d between central LPS injections, or both i.p. and centrally, inhibited production of TNF-a within brain tissue. Inhibition of TNF-a protein formation by a-MSH was confirmed by inhibition of TNF-a mRNA. Plasma TNF-a concentration was elevated markedly after central LPS, indicative of an augmented peripheral host response induced by the CNS signal. The increase was inhibited by a-MSH treatments, in relation to inhibition of central TNF-a. Presence within normal mouse brain of mRNA for the a-MSH receptor MC-1 suggests that the inhibitory effects of a-MSH on brain and plasma TNF-a might be mediated by this receptor subtype. The inhibitory effect of a-MSH on brain TNF-a did not depend on circulating factors because the effect also occurred in brain tissue in vitro. This indicates that a-MSH can act directly on brain cells to inhibit their production of TNF-a. If central TNF-a contributes to pathology in CNS disease and injury, and promotes inflammation in the periphery, agents that act on brain a-MSH receptors should decrease the pathological TNF-a reaction and promote tissue survival.