Caged Dexamethasone to Photo-control the Development of Embryos through Activation of the Glucocorticoid Receptor.

Efficient tools for controlling molecular functions with exquisite spatiotemporal resolution are much in demand to investigate biological processes in living systems. Here we report an easily synthesized caged dexamethasone for photo-activating cytoplasmic proteins fused to the glucocorticoid receptor. In the dark, it is stable in vitro as well as in vivo in both zebrafish (Danio rerio) and Xenopus sp, two significant models of vertebrates. In contrast, it liberates dexamethasone upon UV illumination, which has been harnessed to interfere with developmental steps in embryos of these animals. Interestingly, this new system is biologically orthogonal to the one for photo-activating proteins fused to the estrogen ERT receptor, which brings great prospect for activating two distinct proteins down to the single cell level.

Targeting glucocorticoid side effects: selective glucocorticoid receptor modulator or glucocorticoid-induced leucine zipper? A perspective.

Glucocorticoids (GCs) are steroid hormones that are necessary for life and important in health and disease. They regulate crucial homeostatic functions, including metabolism, cell growth, and development. Although GCs are regulated by circadian rhythm, increased production is associated with stress. Synthetic GCs are a valuable resource for anti-inflammatory and immunosuppressive therapy. Natural and synthetic GCs transduce signals mainly through GC receptor (GR) activation. Extensive research has explored the downstream targets of the GR, and optimization of GC therapy has required collaborative efforts. One highly promising approach involves new dissociative GR modulators. Because transrepression and transactivation of GR genes induce beneficial and adverse effects, respectively, this approach favors transrepression. Another approach involves the use of GC-dependent genes to generate proteins to mediate therapeutic GC effects. In a third approach, drug discovery is used to identify agents that selectively target GR isoforms to obtain differential gene transcription and effects. In this review, we focus on mechanisms of GR function compatible with the use of dissociative drugs. We highlight GC-induced leucine zipper (GILZ), a gene cloned in our laboratory, as a mediator of GC anti-inflammatory and immunosuppressive effects, to outline our perspective on the future of GC therapy.

Greater glucocorticoid receptor activation in hippocampus of aged rats sensitizes microglia.

Healthy aging individuals are more likely to suffer profound memory impairments following an immune challenge than are younger adults. These challenges produce a brain inflammatory response that is exaggerated with age. Sensitized microglia found in the normal aging brain are responsible for this amplified response, which in turn interferes with processes involved in memory formation. Here, we examine factors that may lead aging to sensitize microglia. Aged rats exhibited higher corticosterone levels in the hippocampus, but not in plasma, throughout the daytime (diurnal inactive phase). These elevated hippocampal corticosterone levels were associated with increased hippocampal 11ß-hydroxysteroid dehydrogenase type 1 protein expression, the enzyme that catalyzes glucocorticoid formation and greater hippocampal glucocorticoid receptor (GR) activation. Intracisternal administration of mifepristone, a GR antagonist, effectively reduced immune-activated proinflammatory responses, specifically from hippocampal microglia and prevented Escherichia coli-induced memory impairments in aged rats. Voluntary exercise as a therapeutic intervention significantly reduced total hippocampal GR expression. These data strongly suggest that increased GR activation in the aged hippocampus plays a critical role in sensitizing microglia.