Oxytocin and Steroid Actions.

Biosynthesis and secretion of the hypothalamic nonapeptide oxytocin largely depends on steroid hormones. Estradiol, corticosterone, and vitamin D seem to be the most prominent actors. Due to their lipophilic nature, systemic steroids are thought to be capable of crossing the blood-brain barrier, thus mediating central functions including neuroendocrine and behavioral control. The actual mode of action of steroids in hypothalamic circuitry is still unknown: Most of the oxytocinergic perikarya lack nuclear steroid receptors but express proteins suspected to be membrane receptors for steroids. Oxytocin expressing neurons contain enzymes important for intrinsic steroid metabolism. Furthermore, they produce and probably liberate specific steroid-binding globulins. Rapid responses to steroid hormones may involve these binding proteins and membrane-associated receptors, rather than classic nuclear receptors and genomic pathways. Neuroendocrine regulation, reproductive behaviors, and stress response seem to depend on these mechanisms.

The separation and quantification of aminochromes using high-pressure liquid chromatography with electrochemical detection.

There is increasing evidence that oxidative stress plays an important role in the pathogenesis of many neurodegenerative diseases including Parkinson's disease (PD). In particular there is support for the participation of oxidized catecholamines in PD. Catecholamines are highly reactive and are readily oxidized to aminochromes. While aminochromes have been shown to be toxic, their formation in oxidative stress and subsequent participation in disease has yet to be confirmed. We propose that the characterization of aminochromes, specifically dopaminochrome, is important in clarifying the role that oxidized catecholamines play in PD. We have developed a novel method for the separation and quantification of aminochromes using high-pressure liquid chromatography with electrochemical detection (HPLC-ED). Our method utilizes the separation principles employed in measuring catecholamines by HPLC except that the electrochemical detection of aminochromes is achieved by reversing the detector's electrode. We have used this method to separate and quantify aminochrome standards, prepared by oxidizing catecholamines with sodium periodate (NaIO(4)) and we have also shown that aminochromes can be measured in plasma and cell lysates. Furthermore, we have characterized aminochromes to facilitate forthcoming studies on aminochromes and the role oxidized catecholamines may play in neurodegenerative disease.

Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model.

Previous analysis showed that selective inhibitors of five different host inflammatory mediators administered for sepsis, although beneficial with severe sepsis and high-control mortality rates, were ineffective or harmful with less severe sepsis. We hypothesized that severity of sepsis would also influence inhibition of superoxide anion, another inflammatory mediator. To test this, 6-h infusions of M40401, a selective SOD mimetic, or placebo were given to antibiotic-treated rats (n=547) starting 3 h after challenge with differing doses of intravenous Escherichia coli designed to produce low- or high-control mortality rates. There was a positive and significant (P=0.0008) relationship between the efficacy of M40401 on survival rate and control mortality rates. M40401 increased or decreased the log (odds ratio of survival) (means +/- SE), dependent on whether control mortality rates were greater or less than the median (66%) (+0.19 +/- 0.12 vs. -0.25 +/- 0.10, P=0.01). In a subset of animals examined (n=152) at 9 h after E. coli challenge, M40401 increased (mean effect +/- SE compared with control) mean arterial blood pressure (8 +/- 5 mmHg) and decreased platelets (-37 +/- 22 cells x 10(3)/ml) with high-control mortality rates but had opposing effects on each parameter (-3 +/- 3 mmHg and 28 +/- 19 cells x 10(3)/ml, respectively) with low rates (P < or = 0.05 for the differing effects of M40401 on each parameter with high- vs. low-control mortality rates). A metaregression analysis of published preclinical sepsis studies testing SOD preparations and SOD mimetics showed that most (16 of 18) had control mortality rates >66%. However, across experiments from published studies, these agents were less beneficial as control mortality rate decreased (P=0.03) in a relationship not altered (P=not significant) by other variables associated with septic challenge or regimen of treatment and which was similar, compared with experiments with M40401 (P=not significant). Thus, in these preclinical sepsis models, possibly related to divergent effects on vascular function, inhibition of superoxide anion improved survival with more severe sepsis and high-control mortality rates but was less effective or harmful with less severe sepsis. Extrapolated clinically, inhibition of superoxide anion may be most efficacious in septic patients with severe sepsis and a high risk of death.