Substance P antagonist blocks leakage and reduces activation of cytokine-stimulated rat brain endothelium.
We recently demonstrated that substance P mediates increased permeability of brain endothelium exposed to HIV-1 gp120. To test whether substance P is involved in immune processes at the blood-brain barrier (BBB), we stimulated rat brain endothelial cultures prepared from cerebral microvessels with Interferon-gamma (IFN-gamma) and Tumor necrosis factor-alpha (TNF-alpha), two proinflammatory cytokines that alter the BBB and measured permeability to albumin and expression of adhesion molecule ICAM-1 and MHC class II antigen in the presence and absence of spantide, a powerful substance P antagonist. In a dose-dependent manner, spantide completely neutralized increased permeability induced by TNF-alpha and IFN-gamma and expression of MHC class II molecule induced by IFN-gamma and prevented associated cell morphological changes as revealed by scanning electron microscope. Spantide also reduced expression of ICAM-1 induced by TNF-alpha and IFN-gamma by 35% and 30%, respectively. Substance P mRNA was found in unstimulated brain endothelial cells and was upregulated after stimulation with TNF-alpha and IFN-gamma. These in vitro findings demonstrate that substance P plays a major pathogenetic role in damaging and activating the BBB vascular component in the presence of proinflammatory cytokines.
Annunziata
Pasquale
P
Institute of Neurological Sciences, University of Siena, Viale Bracci, 2, 53100, Siena, Italy. annunziata@unisi.it
Cioni
Chiara
C
Santonini
Riccardo
R
Paccagnini
Eugenio
E
D000418:Albumins / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000418:Albumins; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D013373:Substance P; D007371:Interferon-gamma; C042867:spantide