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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]