Suppression of autoimmune encephalomyelitis by a neurokinin-1 receptor antagonist — A putative role for substance P in CNS inflammation

• Published in: Journal of neuroimmunology 2006-10, Vol.179 (1), p.1-8
• Main Authors: Nessler, Stefan, Stadelmann, Christine, Bittner, Alwina, Schlegel, Kerstin, Gronen, Felix, Brueck, Wolfgang, Hemmer, Bernhard, Sommer, Norbert
• Format: Article
• Language: English
• Subjects: Adhesion molecules; Adoptive Transfer; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Autoimmune encephalomyelitis; Biphenyl Compounds - pharmacology; Blood-Brain Barrier - drug effects; Central Nervous System - drug effects; Central Nervous System - immunology; Central Nervous System - pathology; Cytokines - drug effects; Cytokines - secretion; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Endothelium, Vascular - drug effects; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; ICAM-1; Immunohistochemistry; Inflammation - immunology; Inflammation - pathology; Inflammation - prevention & control; Intercellular Adhesion Molecule-1 - biosynthesis; Intercellular Adhesion Molecule-1 - drug effects; Mice; Neurokinin-1 Receptor Antagonists; NK-1 receptor; Substance P; Substance P - immunology; T-Lymphocytes - drug effects; Vascular Cell Adhesion Molecule-1 - biosynthesis; Vascular Cell Adhesion Molecule-1 - drug effects; VCAM-1
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/j.jneuroim.2006.06.026

Substance P (SP) is an excitatory neurotransmitter in the central and peripheral nervous system. Most of its physiological functions are mediated through binding to the neurokinin-1 receptor (NK-1R). Recently, proinflammatory properties of SP have been described. In this study we utilized T cell transfer experimental autoimmune encephalomyelitis (EAE) to investigate the role of SP in CNS autoimmune disease. Treatment with the NK-1R antagonist CP-96,345 dramatically reduced clinical and histological signs of EAE if administered before disease onset. The protective effect of CP96,345 treatment was related to a reduced expression of the adhesion molecules ICAM-1 and VCAM-1 on CNS endothelia. The cellular composition or activation status of splenocytes was not affected by CP-96,345 administration, while the secretion of proinflammatory Th1 cytokines was reduced in treated animals. Th2 cytokines remained largely unaffected by NK-1 receptor antagonist treatment. In summary, our findings suggest that the protective effect of CP96,345 treatment is mediated by stabilization of the blood–brain barrier and suppression of Th1 immunity.