title: Atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex.
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.
authors: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil.
authors: Clarissa Vasconcelos
authors: CV
authors: de Oliveira
authors: Vinícius Rafael
authors: VR
authors: Funck
authors: Letícia Meier
authors: LM
authors: Pereira
authors: Jéssica
authors: J
authors: Grigoletto
authors: Leonardo Magno
authors: LM
authors: Rambo
authors: Leandro Rodrigo
authors: LR
authors: Ribeiro
authors: Luiz Fernando Freire
authors: LF
authors: Royes
authors: Ana Flávia
authors: AF
authors: Furian
authors: Mauro Schneider
authors: MS
authors: Oliveira
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D000069059:Atorvastatin; D013482:Superoxide Dismutase