Extracellular phospholipase A2 inhibitors suppress central nervous system inflammation.
Phospholipase A2 (PLA2) plays a key role in the production of proinflammatory mediators, namely the arachidonic acid-derived eicosanoids, lysophospholipids, and platelet-activating factor, and indirectly influences the generation of cytokines, nitric oxide (NO), and free radicals. Accordingly, regulation of its activity is important in the treatment of inflammation. Since the main site of PLA2 action in inflammatory processes is the cell membrane, we synthesized extracellular PLA2 inhibitors (ExPLIs) composed of N-derivatized phosphatidyl-ethanolamine linked to polymeric carriers. These membrane-anchored lipid conjugates do not penetrate the cell and interfere with vital phospholipid metabolism or cell viability. The ExPLIs markedly inhibited central nervous system inflammation. This was reflected by the suppressed production and secretion of lipopolysaccharide-induced sPLA2, prostaglandin E2, and NO by glial cells and by the amelioration of experimental autoimmune encephalomyelitis in rats and mice.
Pinto
Florence
F
Laboratory of Neuroimmunology, Department of Neurology, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel.
Brenner
Talma
T
Dan
Phyllis
P
Krimsky
Miron
M
Yedgar
Saul
S
D000818:Animals; D002266:Carboxymethylcellulose Sodium / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004338:Drug Combinations; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000201:enzymology; D005260:Female; D006820:Hyaluronic Acid / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D054467:Phospholipases A2; D051381:Rats; D011917:Rats, Inbred Lew
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D010714:Phosphatidylethanolamines; D009569:Nitric Oxide; D006820:Hyaluronic Acid; D010741:Phospholipases A; D054467:Phospholipases A2; D002266:Carboxymethylcellulose Sodium