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.

Simvastatin improves olanzapine-induced dyslipidemia in rats through inhibiting hepatic mTOR signaling pathway

“…To maximize the efficacy and achieve the greatest statin concentration, 3.0 mg/kg (t.i.d) of Sim was orally administered 3 times/day to the rats in this study, which was equal to 30 mg of drug for a patient in 1 day. Other studies have reported favorable lipid-lowing effects of simvastatin at this concentration [51,52].…”

Effects of Simvastatin Beyond Dyslipidemia: Exploring Its Antinociceptive Action in an Animal Model of Complex Regional Pain Syndrome-Type I

“…Statins may exert anti-inflammatory action through inhibition of microglia and astrocytes cells, according to previously described ( Cordle and Landreth, 2005 ; Lindberg et al, 2005 ; Li et al, 2009 ). More precisely, simvastatin have showed its anti-inflammatory properties in different other preclinical studies ( Higuita-Castro et al, 2016 ; Wang et al, 2016 ; Barbosa et al, 2017 ). In addition, Qiu and colleagues ( Qiu et al, 2016 ) showed that simvastatin attenuated neuropathic pain through inhibition of RhoA/LIMK/Cofilin pathway, which is activated after chronic constriction injury and related to actin dynamic regulation ( Qiu et al, 2016 ).…”

Implications on the Therapeutic Potential of Statins via Modulation of Autophagy

“…The beneficial characteristics of statins are not confined to lowering lipids and improvement of dyslipidemia. Statins also have several properties that potentiate them in the respective therapy of different disorders, including anti-inflammatory [ 74 , 75 ], antioxidant [ 76 , 77 ], neuroprotective [ 78 , 79 ], and antitumor [ 80 ]. Consumption of statins has also been related to a decreased rate of Alzheimer's disease and the development of dementia [ 81 ].…”