Peptide Modulation of Inflammatory Processes within the Brain

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Abstract
It is clear that inflammatory processes contribute to neurodegenerative disease, stroke, closed head injury, encephalitis, and other CNS disorders. These inflammatory processes are marked by local increases in cytokines, in particular tumor necrosis factor-α (TNF-α). It is important to control such CNS inflammation in order to preserve neural function. The neuroimmunomodulatory peptide α-melanocyte-stimulating hormone (α-MSH) has been shown to modulate peripheral inflammation by acting on melanocortin receptors in host cells (macrophages, neutrophils) to inhibit production of such proinflammatory agents. Our results indicate that α-MSH likewise acts directly within the brain to modulate local inflammation. To determine if microglia are involved in anti-inflammatory responses to α-MSH within the brain, murine cells were tested; they produced TNF-α and nitric oxide in response to challenge, and production of both was reduced by α-MSH. In tests on human astrocytes, both α-MSH (1–13) and α-MSH (11–13) reduced TNF-α. Ischemia/reperfusion in the posterior circulation in dogs causes inflammatory reactions and disturbance of function, estimated from decreases in auditory-evoked potentials. These deficits were reduced by administering α-MSH systemically during reperfusion, moreso when the peptide was given during both ischemia and reperfusion. The results indicate that, much as for inflammation in the periphery, α-MSH modulates brain inflammatory responses mediated by proinflammatory agents.