RESUMO
Oxidative stress due to free radical formation is an important mechanism of secondary brain damage following traumatic brain injury (TBI). Phenothiazine has been found to be a strong antioxidant in eukaryotic cells in vitro and in invertebrates in vivo. The present study was designed to determine the neuroprotective potency of unsubstituted phenothiazine in a paradigm of acute brain injury. Thirty minutes after pneumatic, controlled cortical impact (CCI) injury, C57BI6 mice were randomly assigned to "low dose" (3 mg/kg, LD) or "high dose" (30 mg/kg, HD) s.c. phenothiazine or vehicle treatment. Brain lesion, neurofunctional impairment, body weight, and markers of cerebral inflammation were determined 24h after the insult. Phenothiazine treatment dose-dependently reduced brain lesion volume (LD: -19.8%; HD: -26.1%) and posttraumatic body weight loss. There were no significant differences in the neurological function score and in markers of cerebral inflammation (Iba-1 positive cells, TNFα expression), whereas iNOS expression was significantly lower compared to vehicle-treated animals. Phenothiazine appears to modify in a post-treatment protocol certain aspects of secondary brain damage in vivo at unusually low concentrations, in particular the cortical contusion volume after TBI. The potential role of the reduced iNOS expression is unclear at present.
Assuntos
Antioxidantes/farmacologia , Lesões Encefálicas/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Fenotiazinas/farmacologia , Animais , Antioxidantes/uso terapêutico , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Contagem de Células , Relação Dose-Resposta a Droga , Expressão Gênica , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Neuroglia/metabolismo , Neuroglia/patologia , Fenotiazinas/uso terapêutico , Distribuição AleatóriaRESUMO
Statins are the most widely used drugs for the treatment of hypercholesterolemia. In spite of their overall favorable safety profile, they do possess serious myotoxic potential, whose molecular origin has remained equivocal. Here, we demonstrate in cultivated myoblasts and skeletal muscle cells that cerivastatin at nanomolar concentrations interferes with selenoprotein synthesis and evokes a heightened vulnerability of the cells toward oxidative stressors. A correspondingly increased vulnerability was found with atorvastatin, albeit at higher concentrations than with cerivastatin. In selenium-saturated cells, cerivastatin caused a largely indiscriminate suppression of selenoprotein biosynthesis and reduced the steady state-levels of glutathione peroxidase 1 (GPx1) and selenoprotein N (SelN). Selenite, ebselen, and ubiquinone were unable to prevent the devitalizing effect of statin treatment, despite the fact that the cellular baseline resistance against tert-butyl hydroperoxide was significantly increased by picomolar sodium selenite. Mevalonic acid, in contrast, entirely prevented the statin-induced decrease in peroxide resistance. These results indicate that muscle cells may be particularly susceptible to a statin-induced suppression of essential antioxidant selenoproteins, which provides an explanation for the disposition of these drugs to evoke adverse muscular side-effects.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Mioblastos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Piridinas/toxicidade , Selenoproteínas/metabolismo , Animais , Atorvastatina , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ácidos Heptanoicos/toxicidade , Peróxido de Hidrogênio , Ácido Mevalônico/análogos & derivados , Camundongos , Pirróis/toxicidade , Ratos , Selênio/metabolismo , Selênio/farmacologia , Selenoproteínas/genéticaRESUMO
Statins are possibly the most effective drugs for the prevention and treatment of hypercholesterolaemia and coronary heart disease. They are generally well tolerated, however, they do cause some unusual side-effects with potentially severe consequences, most prominently myopathy or rhabdomyolysis and polyneuropathy. We noted that the pattern of side-effects associated with statins resembles the pathology of selenium deficiency, and postulated that the mechanism lay in a well established, but often overlooked, biochemical pathway--the isopentenylation of selenocysteine-tRNA([Ser]Sec). A negative effect of statins on selenoprotein synthesis does seem to explain many of the enigmatic effects and side-effects of statins, in particular, statin-induced myopathy.