Brain Oxidative Stress During Experimental Sepsis Is Attenuated by Simvastatin Administration Carlos Henrique Rocha Catalão 1 & Nilton Nascimento Santos-Júnior 1 & Luís Henrique Angenendt da Costa 1 & Anderson Oliveira Souza 2 & Luciane Carla Alberici 2 & Maria José Alves Rocha 3 Received: 4 July 2016 /Accepted: 12 October 2016 # Springer Science+Business Media New York 2016 Abstract During sepsis, brain damage is associated with oxidative stress due to overproduction of reactive oxy- gen 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 an- tioxidant properties of simvastatin and its possible neu- roprotective 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 ani- mal 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 cat- alase activity ( P < 0.01), citrate synthase enzyme (P < 0.05), and normalized GSH/GSSG ratio. In addi- tion, the histopathological analysis showed a reduction (P < 0.001) in reactive astrocytes and caspase 3-positive apoptotic cells. The results suggest a possible neuropro- tective 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. Keywords HMG-CoA inhibitors . Septic encephalopathy . ROS . Antioxidants Introduction Sepsis and septic shock are among the most frequent causes of morbidity and mortality in Intensive Care Unit (ICU) all over the world. The cognitive and physical disability that can hap- pen in patients that survive sepsis result from several physio- logical alterations induced by a complex immunological re- sponse during the disease [1]. Inflammatory mediators such as tumoral necrosis factor (TNF), reactive oxygen species (ROS) and nitrogen species (RNS) like nitric oxide released by leu- kocytes in the infection focus or in the blood can directly or indirectly reach the brain [2, 3]. Clinical data show that septic encephalopathy (SE), a brain dysfunction observed in septic patients without direct brain infection, can affect 8 to 70 % of the patients, depending mainly on the inclusion criteria used in these studies [2, 4, 5]. Moreover, SE can also be an indepen- dent predictor of mortality [5, 6]. * Maria José Alves Rocha mjrocha@forp.usp.br 1 Department of Neurosciences and Behavioral Sciences of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil 2 Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil 3 Department of Morphology, Physiology and Basic Pathology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil Mol Neurobiol DOI 10.1007/s12035-016-0218-3