Abstract
Statins are among the most prescribed drugs in recent clinical practice. They are also known for their pleiotropic actions, which are independent of their lipid-lowering properties. The effect of lovastatin was investigated against carrageenan-induced paw edema in male Wistar rats (200-250 g) and on leukocyte migration, as measured by carrageenan-induced peritonitis in male Swiss mice (20-25 g), which are models of acute inflammation. Lovastatin (administered 1 h prior to carrageenan), at oral doses of 2, 5, and 10 mg/kg, markedly attenuated paw edema formation in rats at the 4th hour after carrageenan injection (25, 43, and 37% inhibition, respectively). Inhibitions of 20, 45 and 80% were observed in the leukocyte migration, as evaluated by carrageenan-induced peritonitis in mice with lovastatin doses of 0.5, 1 and 5 mg/kg, as compared to controls. Furthermore, lovastatin (administered 1 h before initiation) reduced the nociceptive effect of the formalin test in mice, at both phases, at doses of 2, 5, and 10 mg/kg: first phase (51, 65, and 70%, respectively) and second phase (73, 57, and 66% inhibition of licking time, respectively). The anti-nociceptive activity of lovastatin was inhibited by naloxone (3 mg/kg, sc). Lovastatin (0.01, 0.1, and 1 µg/mL) inhibited by 23, 79, and 86%, respectively, the release of myeloperoxidase from human neutrophils. Leukocyte (predominantly neutrophils) infiltration was almost completely reduced by lovastatin treatment, as observed in the model of acute paw edema with hematoxylin and eosin staining. In addition, lovastatin decreased the number of cells expressing tumor necrosis factor-α (TNF-α) and the inducible form of nitric oxide synthase (iNOS) activity. Therefore, the alterations in leukocyte activity and cytokine release could contribute to the anti-inflammatory activity of lovastatin.
Highlights
In the early 80’s, the statins, a new therapeutic class, were introduced as lipid-lowering agents
We investigated the effects of lovastatin on in vitro myeloperoxidase (MPO) release and on tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase-expressing cells, and on rat paws after carrageenaninduced edema
Statins inhibit the conversion of hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonic acid, and down-regulate the production of bioactive sterols derived from the cholesterol synthesis pathway
Summary
In the early 80’s, the statins, a new therapeutic class, were introduced as lipid-lowering agents. Since their role in the reduction of serum lipids has been extensively investigated in both experimental and clinical trials [1]. Statins are among the most widely used prescription drugs, and exert their lipid-lowering actions by reversible and competitive inhibition of the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), the rate-limiting step in the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of cholesterol [2]. Statins are known for their pleiotropic effects, which are independent of their lipid-lowering properties [4]. Among the effects of statins, the most relevant are anti-atherosclerotic [5] and anti-inflammatory actions [6], improvement of endothelial dysfunction [7], anti-thrombosis [8] and anti-oxidant [9] actions, prevention of Alzheimer’s disease [10], and antineoplasic actions [3]
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