, 2009). It has been suggested that guanosine

(GUA) exhibits neuroprotective effects in a variety of in vitro and in vivo models of neurotoxicity that involve the over-activation of glutamatergic receptors ( Schmidt et al., 2007). The exact molecular mechanism(s) involved in the neuroprotection afforded by GUA is still unknown, but seems to be related to a decrease of extracellular glutamate levels, by stimulating astrocytic glutamate uptake ( Frizzo et al., 2001 and Schmidt et al., 2007). In the light of this knowledge, the aim of our study was to investigate the protective effect of GUA in rats against sepsis-induced oxidative stress in key brain regions associated with sepsis and in cognitive dysfunction.

Male Wistar rats (2–3 months, 220–310 g) CP868596 were obtained from our breeding colony at UNESC. The animals were housed in groups of five per cage with food and water available ad libitum, and were maintained on a 12 h light/dark cycle (lights on at 7:00 am). All experimental procedures APO866 in vitro involving animals were performed in accordance with the guidelines established by the National Institutes of Health (Bethesda, Md) Guide for Care and Use of Laboratory Animals and the Brazilian Society for Neuroscience and Behavior (SBNeC) recommendations for animal care. All protocols performed were approved by the ethics committee of UNESC. Rats were subjected to CLP as previously described (Ritter et al., 2003). Briefly, they were anesthetized with a mixture of ketamine (80 mg/kg) and xylazine (10 mg/kg), given intraperitoneally. Under aseptic conditions, a 3-cm midline laparotomy was performed to expose the cecum and adjoining intestine. The cecum was tightly ligated with a 3.0 silk C-X-C chemokine receptor type 7 (CXCR-7) suture at its base, below the ileocecal valve, and was perforated once with 14-gauge needle. The cecum was then squeezed gently to extrude a small amount of feces through the perforation site. The cecum was then returned to the peritoneal cavity, and the laparotomy was

closed with 4.0 silk sutures. Animals were resuscitated with regular saline (50 mL/kg) subcutaneously (s.c.) immediately after and 12 h after CLP. All animals received basic support (saline at 50 mL/kg immediately after and 12 h after CLP plus antibiotics (ceftriaxone at 30 mg/kg and clindamycin 25 mg/kg) every 6 h, s.c. All animals were returned to their cages with free access to food and water. In the sham-operated group, the rats were submitted to all surgical procedures but the cecum was neither ligated nor perforated. GUA obtained from Sigma (St. Louis, MO, USA) was dissolved in 10 μM NaOH. The solutions were prepared immediately before use and were protected from the light during the experiments. Immediately after CLP, rats received either daily intraperitoneal (i.p.