alpha-MSH peptides inhibit production of nitric oxide and tumor necrosis factor-alpha by microglial cells activated with beta-amyloid and interferon gamma

alpha-Melanocyte stimulating hormone (alpha-MSH) is an ancient tridecapepti de with potent inhibitory activity in all major forms of inflammation. The anti-inflammatory message sequence of alpha-MSH resides in the COOH-termina l tripeptide alpha-MSH[11-13]. We tested the influence of alpha-MSH[1-13] a nd of alpha-MSH[11-13] in a cultured murine microglia cell line known to pr oduce nitric oxide (NO2-) and tumor necrosis factor (TNF alpha) when stimul ated with beta-amyloid protein (A beta). Melanocortin peptides significantl y inhibited release of both NO2- and TNF alpha into cell-free supernatants from microglia stimulated with A beta[1-42] or A beta[25-35] peptides and i nterferon gamma (IFN gamma). Northern blot analysis demonstrated that alpha -MSH[1-13] and alpha-MSH[11-13] inhibited accumulation of inducible nitric oxide synthase (iNOS) and TNF alpha mRNA was triggered by A beta stimulatio n. A beta/microglial interaction is believed to promote the progression of inflammatory and neurodegenerative changes in senile plaques in Alzheimer's disease. Our data indicate that alpha-MSH peptides might be used to modula te the local response of the brain to A beta deposition in this neurodegene rative disease. (C) 1999 Academic Press.