Substance P antagonist blocks leakage and reduces activation of cytokine-stimulated rat brain endothelium

• Published in: Journal of neuroimmunology Vol. 131; no. 1; pp. 41 - 49
• Main Authors: Annunziata, Pasquale, Cioni, Chiara, Santonini, Riccardo, Paccagnini, Eugenio
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2002
• Subjects: Adhesion molecules; Albumins - metabolism; Animals; Blood-Brain Barrier - drug effects; Blood–brain Barrier; Brain - blood supply; Brain - cytology; Brain - metabolism; Brain endothelium; Cells, Cultured; Cytokines; Cytokines - antagonists & inhibitors; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - ultrastructure; Histocompatibility Antigens Class II - metabolism; Intercellular Adhesion Molecule-1 - metabolism; Interferon-gamma - antagonists & inhibitors; Rats; Rats, Sprague-Dawley; RNA, Messenger - biosynthesis; Substance P; Substance P - analogs & derivatives; Substance P - antagonists & inhibitors; Substance P - biosynthesis; Substance P - genetics; Substance P - pharmacology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Blood–brain Barrier; Brain endothelium; Adhesion molecules; Cytokines; Substance P
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/S0165-5728(02)00262-X

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-γ (IFN-γ) and Tumor necrosis factor-α (TNF-α), 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-α and IFN-γ and expression of MHC class II molecule induced by IFN-γ and prevented associated cell morphological changes as revealed by scanning electron microscope. Spantide also reduced expression of ICAM-1 induced by TNF-α and IFN-γ by 35% and 30%, respectively. Substance P mRNA was found in unstimulated brain endothelial cells and was upregulated after stimulation with TNF-α and IFN-γ. 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.