title: Brain Oxidative Stress During Experimental Sepsis Is Attenuated by Simvastatin Administration.
abstract: During sepsis, brain damage is associated with oxidative stress due to overproduction of reactive oxygen species (ROS). Although there are recent reports about the benefits of statins in experimental sepsis and endotoxemia in peripheral organs, little is known about their effects in the CNS. Here, we investigated the antioxidant properties of simvastatin and its possible neuroprotective role during experimental sepsis. Male Wistar rats (250-300 g) were submitted to cecal ligation and puncture (CLP, n = 34) or remained as non-manipulated (naive, n = 34). Both groups were treated by gavage with simvastatin (20 mg/kg) or an equivalent volume of saline. The animals submitted to CLP were treated 4 days before and 48 h after surgery. One animal group was decapitated and the blood and brain were collected to quantify plasma levels of cytokines and assess astrogliosis and apoptosis in the prefrontal cortex and hippocampus. Another group was perfused with PBS (0.01 M), and the same brain structures were dissected to analyze oxidative damage. The CLP rats treated with simvastatin showed a reduction in nitric oxide (P < 0.05), IL1-β (P < 0.001), IL-6 (P < 0.01), and TBARS levels (P < 0.001) and an increase in catalase activity (P < 0.01), citrate synthase enzyme (P < 0.05), and normalized GSH/GSSG ratio. In addition, the histopathological analysis showed a reduction (P < 0.001) in reactive astrocytes and caspase 3-positive apoptotic cells. The results suggest a possible neuroprotective effect of simvastatin in structures responsible for spatial learning and memory and indicate the need for behavioral studies evaluating the impact on cognitive damage, as frequently seen in patients surviving sepsis.
authors: Department of Neurosciences and Behavioral Sciences of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors: Carlos Henrique Rocha
authors: CHR
authors: Catalão
authors: Department of Neurosciences and Behavioral Sciences of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors: Nilton Nascimento
authors: NN
authors: Santos-Júnior
authors: Department of Neurosciences and Behavioral Sciences of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors: Luís Henrique Angenendt
authors: LHA
authors: da Costa
authors: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors: Anderson Oliveira
authors: AO
authors: Souza
authors: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors: Luciane Carla
authors: LC
authors: Alberici
authors: Department of Morphology, Physiology and Basic Pathology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. mjrocha@forp.usp.br.
authors: Maria José Alves
authors: MJA
authors: Rocha
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D002432:Cecum / Q000473:pathology; D002950:Citrate (si)-Synthase / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology; D008026:Ligation; D008297:Male; D008954:Models, Biological; D009566:Nitrates / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000201:enzymology; D011677:Punctures; D017208:Rats, Wistar; D018805:Sepsis / Q000097:blood / Q000473:pathology*; D019821:Simvastatin / Q000008:administration & dosage* / Q000494:pharmacology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D009566:Nitrates; D017392:Thiobarbituric Acid Reactive Substances; D019821:Simvastatin; D002950:Citrate (si)-Synthase; D053148:Caspase 3
keywords: Antioxidants; HMG-CoA inhibitors; ROS; Septic encephalopathy