title: Effects of Ezetimibe, Simvastatin, and their Combination on Inflammatory Parameters in a Rat Model of Adjuvant-Induced Arthritis.
abstract: Statins are hypocholesterolemic drugs that are prescribed for patients with an increased risk of cardiovascular and cerebrovascular complications. Ezetimibe has an atheroprotective activity through inhibition of the expression of vascular adhesion molecule-I and vascular CD14, a marker of the infiltration of mononuclear leukocytes. Ezetimibe reduces the amount of chemoattractant protein-1 that is available for monocytes and macrophages and alters the activity of nuclear factor κB in leukocytes. The mechanisms of action of statins complement those of ezetimibe. Previous studies have demonstrated that the combination of statins and ezetimibe has beneficial effects, including antiinflammatory activity. The present study evaluated the effects of monotherapy with ezetimibe and simvastatin compared with ezetimibe + simvastatin combined on the evolution of the inflammatory response in a rat model of Complete Freund's Adjuvant-induced arthritis. The animals were treated with 10 mg/kg ezetimibe, 40 mg/kg simvastatin, or 10 mg/kg ezetimibe + 40 mg/kg simvastatin for 1, 7, 14, or 28 days. We analyzed leukocyte rolling behavior, leukocyte adhesion to the endothelium, the number of leukocytes that were recruited to the knee joint cavity, and the concentration of cytokines that are involved in the inflammatory response. The data were analyzed using paired t tests or analysis of variance followed by Bonferroni post hoc test. The treatments reduced leukocyte rolling behavior and leukocyte adhesion. The monotherapies did not change the number of leukocytes that were recruited to the knee joint cavity, whereas the ezetimibe + simvastatin combination significantly reduced this parameter. The treatments reduced the levels of proinflammatory cytokines and increased the levels of the antiinflammatory cytokine IL-10, indicating antiinflammatory properties of these drugs in this experimental model of inflammation.
authors.affiliation: Department of Pharmacology and Therapeutics of the State University of Maringá, Maringá, PR, Brazil.
authors.forename: Carmem Patrícia
authors.initials: CP
authors.lastname: Barbosa
authors.affiliation: Department of Biochemistry of the State University of Maringá, Maringá, PR, Brazil.
authors.forename: Lívia
authors.initials: L
authors.lastname: Bracht
authors.affiliation: Department of Pharmacology and Therapeutics of the State University of Maringá, Maringá, PR, Brazil.
authors.forename: Franciele Queiroz
authors.initials: FQ
authors.lastname: Ames
authors.affiliation: Department of Pharmacology and Therapeutics of the State University of Maringá, Maringá, PR, Brazil.
authors.forename: Francielli Maria
authors.initials: FM
authors.lastname: de Souza Silva-Comar
authors.affiliation: Fellowship (medicine) of the State University of Maringá, Maringá, PR, Brazil.
authors.forename: Rafael Prizon
authors.initials: RP
authors.lastname: Tronco
authors.affiliation: Department of Pharmacology and Therapeutics of the State University of Maringá, Maringá, PR, Brazil. cabamado@uem.br.
authors.forename: Ciomar Aparecida
authors.initials: CA
authors.lastname: Bersani-Amado
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004359:Drug Therapy, Combination / Q000379:methods; D000069438:Ezetimibe / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy*; D007719:Knee Joint / Q000473:pathology; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000378:metabolism; D051381:Rats; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D019821:Simvastatin; D000069438:Ezetimibe
keywords: adjuvant-induced arthritis; cell adhesion; cytokine; ezetimibe; rolling behavior; simvastatin