Peptide modulation of fever and inflammation within the brain

The importance of melanocortin peptides to host responses was recognized with the observation of the antipyretic effect of centrally administered alpha-melanocyte stimulating hormone (alpha-MSH). It is now clear that this neuropeptide also exerts remarkable antiinflammatory activity via direct actions on peripheral host cells, descending neurogenic antiinflammatory pathways stemming from CNS melanocortin receptors, and local actions on receptors that control inflammation within the brain. Recent studies of the latter influence indicate that alpha-MSH inhibits brain tumor necrosis factor-alpha (TNF-alpha), previously linked to human neurodegenerative diseases, induced by local injection of lipopolysaccharide. Ischemia/reperfusion of the brain, a model of stroke, induces inflammation marked by disturbance of CNS function. alpha-MSH given systemically modulates disturbances of auditory evoked potentials induced by ischemia/reperfusion in the posterior circulation. Such influences of the peptide may occur through inhibition of inflammatory agents produced by glia: alpha-MSH 1-13 and 11-13 modulate TNF-alpha and nitric oxide produced by activated murine microglia, and TNF-alpha produced by human astrocytes. Because glia can secrete alpha-MSH and express melanocortin receptors, they may, like peripheral macrophages, contain autocrine regulatory circuits based on the peptide. alpha-MSH thus modulates both fever and inflammation in the brain by acting on local melanocortin receptors.