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

Abstract

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

Central Neurotranspeptide, Alpha-Melanocyte-Stimulating Hormone (.ALPHA.-MSH) is Upregulated in Patients with Congestive Heart Failure

“…Inflammation is reduced by α-MSH via direct and indirect mechanisms (25) (27,28 (30,31), α-MSH may be one of the therapeutic targets of CHF in the future (32,33). IL-10 is also considered to be one of the therapeutic targets for acute myocarditis and heart failure (12,32,33).…”

Elevated plasma levels of α-melanocyte stimulating hormone (α-MSH) are correlated with insulin resistance in obese men

“…5,6 Yaswen et al reported that systemically administered a-MSH may contribute to central inhibition of feeding and peripheral inhibition of free fatty acid uptake as well as to stimulation of lipolysis in mice lacking proopiomelanocortin -derived peptide. 7 Elevated concentrations of a-MSH in HIV-infected patients have been reported, but circulating levels of a-MSH and their role in metabolic abnormalities associated with obesity have not as yet been evaluated.…”

Generation of expression constructs that secrete bioactive αMSH and their use in the treatment of experimental autoimmune encephalomyelitis

“…8,9 aMSH has several known activities including the ability to stimulate melanogenesis, regulate body weight, and inhibit inflammation. [10][11][12][13][14][15] These effects are mediated by cell surface, G-protein-coupled, melanocortin receptors (MC-R). [16][17][18][19] aMSH binding to MC-R1 and MC-R5 activates adenyl cyclase and results in a significant increase of intracellular cAMP.…”

“…22,23 The antiinflammatory activity of aMSH is due in part to inhibition of IkB degradation, 24,25 an effect that prevents the transcription factor nuclear factor kB (NF-kB) from entering the nucleus. NF-kB is required for the production of several pro-inflammatory factors, such as IL-1 and TNF-a 11,12,14,[26][27][28] , and has been shown to have a role in the pathogenesis of many inflammatory/autoimmune diseases. 25 The ability of aMSH to inhibit NF-kB translocation makes it an interesting target for therapeutic intervention.…”

“…25 The ability of aMSH to inhibit NF-kB translocation makes it an interesting target for therapeutic intervention. In fact, aMSH and its analogs have shown therapeutic activity in many animal disease models [11][12][13][14] such as inflammatory bowel disease, 26 arthritis 29 and hepatitis. 27 However, the inherent instability of the peptide does not make it suitable for use as a therapeutic agent in humans.…”