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Abstract: ‘Psychoneuroendocrinology’ is now quickly emerging as a hot interdisciplinary research field that addresses the interplay between neuronal and endocrine signaling in psychiatric diseases. Both glucocorticoid hormones and dopamine have an important role in maintaining normal brain functions. In this review, molecular and mechanistic aspects of glucocorticoid effects on brain function and behavior will be discussed with specific reference to dopamine signaling. [Copyright &y& Elsevier]

The identification of selective glucocorticoid receptor (GR) modifiers, which separate transactivation and transrepression properties, represents an important research goal for steroid pharmacology. Although the gene-activating properties of ER are mainly associated with undesirable side effects, its negative interference with the activity of transcription factors, such as NF-κB, greatly contributes to its antiinflammatory and immune-suppressive capacities. In the present study, we found that Compound A (CpdA), a plant-derived phenyl aziridine precursor, although not belonging to the steroidal class of ER-binding ligands, does mediate gene-inhibitory effects by activating ER. We demonstrate that CpdA exerts an antiinflammatory potential by down-modulating TNF- induced proinflammatory gene expression, such as IL-6 and E- selectin, but, interestingly, does not at all enhance glucocorticoid response element-driven genes or induce ER binding to glucocorticoid response element-dependent genes in viva. We further show that the specific gene-repressive effect of CpdA depends on the presence of functional ER, displaying a differential phosphorylation status with CpdA as compared with dexamethasone treatment. The antiinflammatory mechanism involves both a reduction of the in viva DNA-binding activity of p65 as well as an interference with the transactivation potential of NF-κB. Finally, we present evidence that CpdA is as effective as dexamethasone in counteracting acute inflammation in vivo and does not cause a hyperglycemic side effect. Taken together, this compound may be a lead compound of a class of antiinflammatory agents with fully dissociated properties and might thus hold great potential for therapeutic use. [ABSTRACT FROM AUTHOR]

The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Thl7, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-&kgr;B and its subsequent recruitment onto the I&kgr;B&agr; promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4-induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy. [ABSTRACT FROM AUTHOR]