Atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex

Pharmacol Res. 2013 May:71:1-8. doi: 10.1016/j.phrs.2013.02.003. Epub 2013 Feb 18.

Abstract

Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting step in cholesterol biosynthesis. Statins effectively prevent and reduce the risk of coronary artery disease through lowering serum cholesterol, and also exert anti-thrombotic, anti-inflammatory and antioxidant effects independently of changes in cholesterol levels. On the other hand, clinical and experimental evidence suggests that abrupt cessation of statin treatment (i.e. statin withdrawal) is associated with a deleterious rebound phenomenon. In fact, statin withdrawal increases the risk of thrombotic vascular events, causes impairment of endothelium-dependent relaxation and facilitates experimental seizures. However, evidence for statin withdrawal-induced detrimental effects to the brain parenchyma is still lacking. In the present study adult male Wistar rats were treated with atorvastatin for seven days (10mg/kg/day) and neurochemical assays were performed in the cerebral cortex 30 min (atorvastatin treatment) or 24h (atorvastatin withdrawal) after the last atorvastatin administration. We found that atorvastatin withdrawal decreased levels of nitric oxide and mitochondrial superoxide dismutase activity, whereas increased NADPH oxidase activity and immunoreactivity for the protein nitration marker 3-nitrotyrosine in the cerebral cortex. Catalase, glutathione-S-transferase and xanthine oxidase activities were not altered by atorvastatin treatment or withdrawal, as well as protein carbonyl and 4-hydroxy-2-nonenal immunoreactivity. Immunoprecipitation of mitochondrial SOD followed by analysis of 3-nitrotyrosine revealed increased levels of nitrated mitochondrial SOD, suggesting the mechanism underlying the atorvastatin withdrawal-induced decrease in enzyme activity. Altogether, our results indicate the atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex, and that changes in NADPH oxidase activity and mitochondrial superoxide dismutase activities may underlie such harmful effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atorvastatin
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / enzymology
  • Cerebral Cortex / metabolism*
  • Heptanoic Acids / administration & dosage
  • Heptanoic Acids / adverse effects*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects*
  • Male
  • Nitric Oxide / metabolism
  • Oxidation-Reduction
  • Pyrroles / administration & dosage
  • Pyrroles / adverse effects*
  • Rats
  • Rats, Wistar
  • Substance Withdrawal Syndrome / enzymology
  • Substance Withdrawal Syndrome / etiology*
  • Substance Withdrawal Syndrome / metabolism*
  • Superoxide Dismutase / metabolism
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Pyrroles
  • Nitric Oxide
  • 3-nitrotyrosine
  • Tyrosine
  • Atorvastatin
  • Superoxide Dismutase