Nitroxide Tempol down-regulates kinase activities associated with NADPH oxidase function in phagocytic cells and potentially decreases their fungicidal response.

AIMS: The identification of novel targets to control inflammation in humans is probably the primary challenge that impairs the development of new anti-inflammatory drugs. Therefore, the modulation of intracellular signaling pathways in phagocytes may be an interesting means of achieving this goal. However, this change to signaling can compromise the host's susceptibility to invading pathogens. We investigated whether the antioxidant nitroxide Tempol regulates the activity of kinases associated with the production of oxidants in neutrophils, which affects the fungicidal capability of these cells. MAIN METHODS: The effects of Tempol on PMA- or fMLP-activated neutrophils were examined by oxygen consumption as an index of the oxidative burst, a release of extracellular and total Reactive Oxygen Species (ROS) by chemiluminescence, kinase activities through analysis of ATP consumption during enzyme activities and the dot blot immunoassay and, finally, by neutrophil capacity of killing Candida albicans. KEY FINDINGS: Tempol significantly inhibited the neutrophil oxidative burst in a concentration-dependent manner and decreased oxygen consumption (IC50 = 45 µM) and extracellular/total ROS formation with an increase on the lag period response. In addition, Tempol inhibited neutrophil kinase activities (i.e., a decrease in protein phosphorylation) elicited through different biochemical pathways and consequently impaired the fungicidal activity of these cells. SIGNIFICANCE: Although Tempol has potential anti-inflammatory activity that acts on different intracellular pathways (such as those involving kinases), researchers should be cautious, since this nitroxide down-regulated oxidants production and the fungicidal response of neutrophils.

Prostaglandins mediate depressive-like behaviour induced by endotoxin in mice.

Sickness behaviour appears to be the expression of a central motivational state that reorganises the organism's priorities to cope with infectious pathogens. To evaluate the possible participation of prostaglandins in lipopolysaccharide-induced sickness behaviours, mice were submitted to the tail suspension test (TST), forced swim test (FST), open field test and dark-light box test. Lipopolysaccharide (LPS, 100microg/kg; i.p.) administration increased the time spent immobile in the TST, increased the time spent floating in the FST, and depressed locomotor activity in the open field. Indeed, treatment with LPS decreased the total number of transitions made between the dark and light compartments of the apparatus. Pretreatment with indomethacin (10mg/kg; i.p.) or nimesulide (5mg/kg) blocked behavioural changes induced by LPS in the FTS, TST, open field and light-dark box test. This effect was similar to pretreatment with dexamethasone (1mg/kg), which is a steroidal drug that inhibits immune and inflammatory responses, including cytokine production. These findings confirm previous observations that have reported LPS-induced sickness behaviours. In addition, they provide evidence that the synthesis of prostaglandins is necessary for changes in depressive-like and exploratory behaviours in mice, which is supported by the fact that COX inhibitors also attenuate LPS-induced behavioural changes.