J Neuroimmunol. 2006 Aug 9; [Epub ahead of print]
Suppression of autoimmune encephalomyelitis by a neurokinin-1 receptor antagonist - A putative role for substance P in CNS inflammation.
Nessler S, Stadelmann C, Bittner A, Schlegel K, Gronen F, Brueck W, Hemmer B, Sommer N.
Clinical Neuroimmunology Group, Department of Neurology, Philipps-University, Rudolf-Bultmann-Strasse 8, 35039 Marburg, Germany; Clinical Neuroimmunology Group, Department of Neurology, Heinrich-Heine University, Moorenstrasse 5, 40225 Dusseldorf, Germany.
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. |
