Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease

Mykicki N., Herrmann A., Schwab N., Deenen R., Sparwasser T., Limmer A., Wachsmuth L., Klotz L., Köhrer K., Faber C., Wiendl H., Luger T., Meuth S., Loser K.

Zusammenfassung

In inflammation-associated progressive neuroinflammatory disorders, such as multiple sclerosis (MS), inflammatory infiltrates containing T helper 1 (TH1) and TH17 cells cause demyelination and neuronal degeneration. Regulatory T cells (Treg) control the activation and infiltration of autoreactive T cells into the central nervous system (CNS). In MS and experimental autoimmune encephalomyelitis (EAE) in mice, Treg function is impaired. We show that a recently approved drug, Nle4-D-Phe7-a-melanocyte-stimulating hormone (NDP-MSH), induced functional Treg, resulting in amelioration of EAE progression in mice. NDP-MSH also prevented immune cell infiltration into the CNS by restoring the integrity of the blood-brain barrier. NDP-MSH exerted long-lasting neuroprotective effects in mice with EAE and prevented excitotoxic death and reestablished action potential firing in mouse and human neurons in vitro. Neuroprotection by NDP-MSH was mediated via signaling through the melanocortin-1 and orphan nuclear 4 receptors in mouse and human neurons. NDP-MSH may be of benefit in treating neuroinflammatory diseases such as relapsingremitting MS and related disorders.