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

Abstract

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-α-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 relapsing-remitting MS and related disorders.

• Authors: Nadine Mykicki, Alexander M Herrmann, Nicholas Schwab, René Deenen, Tim Sparwasser, Andreas Limmer, Lydia Wachsmuth, Luisa Klotz, Karl Köhrer, Cornelius Faber, Heinz Wiendl, Thomas A Luger, Sven G Meuth, Karin Loser
• Journal: Science translational medicine (Sci Transl Med) Vol. 8 Issue 362 Pg. 362ra146 (10 26 2016) ISSN: 1946-6242 [Electronic] United States
• PMID: 27797962 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Neuroprotective Agents
• Receptor, Melanocortin, Type 1
• Glutamic Acid
• alpha-MSH
• MSH, 4-Nle-7-Phe-alpha-

Topics

• Action Potentials
• Animals
• Blood-Brain Barrier
• Bone Marrow Cells (metabolism)
• Cell Proliferation
• Central Nervous System (immunology)
• Disease Progression
• Encephalomyelitis, Autoimmune, Experimental (drug therapy)
• Flow Cytometry
• Gene Expression Profiling
• Glutamic Acid (chemistry)
• Hippocampus (metabolism)
• Magnetic Resonance Imaging
• Mice
• Mice, Inbred C57BL
• Neurons (metabolism)
• Neuroprotective Agents (pharmacology)
• Protein Binding
• Receptor, Melanocortin, Type 1 (genetics, metabolism)
• T-Lymphocytes, Regulatory (cytology)
• alpha-MSH (analogs & derivatives, pharmacology)