Suppression of autoimmune encephalomyelitis by a neurokinin-1 receptor antagonist--a putative role for substance P in CNS inflammation.
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.
Nessler
Stefan
S
Clinical Neuroimmunology Group, Department of Neurology, Philipps-University, Rudolf-Bultmann-Strasse 8, Marburg, Germany. stefan.nessler@uni-duesseldorf.de
Stadelmann
Christine
C
Bittner
Alwina
A
Schlegel
Kerstin
K
Gronen
Felix
F
Brueck
Wolfgang
W
Hemmer
Bernhard
B
Sommer
Norbert
N
D019264:Adoptive Transfer; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects; D051379:Mice; D064729:Neurokinin-1 Receptor Antagonists; D013373:Substance P / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D016207:Cytokines; D064729:Neurokinin-1 Receptor Antagonists; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D013373:Substance P; C066892:CP 96345