Recent animal work has suggested that injection of human pCRP can increase myocardial infarct size in a rat myocardial Background-The relevance of the dissociation of circulating pentameric C-reactive protein (pCRP) to its monomeric subunits (mCRP) is poorly understood. We investigated the role of conformational C-reactive protein changes in vivo. Methods and Results-We identified mCRP in inflamed human striated muscle, human atherosclerotic plaque, and infarcted myocardium (rat and human) and its colocalization with inflammatory cells, which suggests a general causal role of mCRP in inflammation. This was confirmed in rat intravital microscopy of lipopolysaccharide-induced cremasteric muscle inflammation. Intravenous pCRP administration significantly enhanced leukocyte rolling, adhesion, and transmigration via localized dissociation to mCRP in inflamed but not noninflamed cremaster muscle. This was confirmed in a rat model of myocardial infarction. Mechanistically, this process was dependent on exposure of lysophosphatidylcholine on activated cell membranes, which is generated after phospholipase A2 activation. These membrane changes could be visualized intravitally on endothelial cells, as could the colocalized mCRP generation. Blocking of phospholipase A2 abrogated C-reactive protein dissociation and thereby blunted the proinflammatory effects of C-reactive protein.Identifying the dissociation process as a therapeutic target, we stabilized pCRP using 1,6-bis(phosphocholine)-hexane, which prevented dissociation in vitro and in vivo and consequently inhibited the generation and proinflammatory activity of mCRP; notably, it also inhibited mCRP deposition and inflammation in rat myocardial infarction. Conclusions-These results provide in vivo evidence for a novel mechanism that localizes and aggravates inflammation via phospholipase A2-dependent dissociation of circulating pCRP to mCRP. mCRP is proposed as a pathogenic factor in atherosclerosis and myocardial infarction. Most importantly, the inhibition of pCRP dissociation represents a promising, novel anti-inflammatory therapeutic strategy. (Circulation. 2014;130:35-50.)

There is evidence that reactive oxygen species (ROS) are involved in the pathophysiology of psychiatric disorders such as schizophrenia. Indirect biochemical alterations of ROS formation have been shown for patients treated with antipsychotics as well as for untreated patients. Only one study measured directly the ROS formation after treatment with antipsychotics by using electron spin resonance spectroscopy. The aim of the present examination was to demonstrate the effects of haloperidol, clozapine and olanzapine in concentrations of 18, 90 and 180 μg/mL on the formation of ROS in the whole blood of rats by using electron spin resonance spectroscopy after incubation for 30 min. To test the protective capacity of vitamin C we incubated the highest concentration of each drug with vitamin C (1 mM). Under all treatment conditions, olanzapine led to a significantly higher formation of ROS compared with control conditions, whereas in the cases of haloperidol and clozapine the two higher concentrations induced a significantly enhanced formation of ROS. Vitamin C reduced the ROS production of all drugs tested and for haloperidol and clozapine the level of significance was reached. Our study demonstrated that antipsychotics induce the formation of ROS in the whole blood of rats, which can be reduced by the application of vitamin C.

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Encephalopathy associated with septic shock as well as psychiatric disorders can be caused by the central nervous formation of reactive oxygen species (ROS) associated with inflammation. The systemic application of lipopolysaccharide (LPS, 100 mug/kg i.p.) also serves as a model for major depression and results in enhanced inflammatory processes. which are characterized by the stimulation of microglia or macrophages that then impair normal brain function. The aim of the present study was to analyze the effect of peripherally applied LPS on the central nervous formation of ROS and IL-6 in wild-type mice and in mice lacking the NADPH oxidase Nox2 subunit gp91phox. Microdialysis was performed in the striatum of the mice. Central nervous ROS were detected by electron spin resonance spectroscopy using 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH) as reactant, which was infused via a microdialysis probe. IL-6 was measured in microdialysis samples by an immunoassay. Finally, blood samples were taken by heart puncture to detect IL-6 in plasma. In the wild-type mice, LPS significantly increased the ROS formation in the striatum of wild-type mice and resulted in a significantly enhanced IL-6 production. In the mice lacking the NADPH oxidase Nox2 subunit gp91phox, LPS did not enhance ROS formation, while central IL-6 was significantly increased. IL-6 plasma values were enhanced in both types of mice. In conclusion, the gp91phox-containing NADPH oxidase complex is involved in the central nervous ROS formation after peripheral LPS stimulation and might be a pharmacological target in patients with septic shock.