ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2016) 44 P166 | DOI: 10.1530/endoabs.44.P166

Corticosteroid-driven response of synaptic plasticity-associated targets are differentially regulated in the rodent brain: transcriptional actions of receptor modulators

Chinedu Udeh-Momoh1,2, Francesca Spiga2, Eleanor Waite3, Fiona Thomson4 & Stafford Lightman2

1Imperial College London, London, UK; 2University of Bristol, Bristol, UK; 3Oxford University, Oxford, UK; 4Glasgow University, Glasgow, UK.

Actions of the stress hormone, glucocorticoid (GC), are essential for the modulation of implicated biological processes such as synaptic transmission. In disease paradigms that feature a hormone hyper-secretion phenotype (e.g. neurocognitive disorders), the normalcy of receptor signaling is compromised.

The pro-cognate role of Glucocorticoid receptor (GR) inhibition via hormone analogues bearing anti-glucocorticoid properties is well described. A key example is RU-486 (Mifepristone), an effective GR blocker. Though widely used experimentally, this compound exhibits partial agonist activity creating a need for potent antagonists that exhibit greater receptor-selectivity. Org A; a novel non-steroidal anti-glucocorticoid is one such candidate. Highly selective for GR, it reverses the deleterious effects of abnormal GC exposure.

Although data exists for the actions of these GR antagonists on signaling parameters like receptor translocation and activation; little is known about their effect on target gene modulation, more-so markers related to synaptic plasticity. Such information is critical since gene regulation is a key mechanism by which GCs modulate such neuronal processes.

In this study, we show that exposure to high GC levels (3 mg/kg i.p.) elicits an increase in plasma corticosterone levels sufficient to induce GR nuclear translocation, and subsequent hormone-mediated receptor activation. These effects remained unaltered by investigated compounds, RU-486 (20 mg/kg s.c.) and Org A (20 mg/kg s.c.).

Differential regulation of synaptic plasticity transcripts (adcy8, sgk-1, pkaca and gria-1 mRNA) were observed in the rodent hippocampus and amygdala. These modulatory effects occurred in a gene and tissue specific manner, with both antagonists eliciting differing transcriptional responses to the GC signal.

Our results provide novel information on the differential effects of select GR antagonists on GC-mediated transcriptional responses. Given the potential use of this class of compounds for targeted- treatment of associated diseases, further research into the reported distinct transcriptional regulation during a hyper-corticosterone state is needed.

Reference: Spiga F, Lightman SL, Differential effect of glucocorticoid receptor antagonists on glucocorticoid receptor nuclear translocation and DNA binding. Journal of Psychopharmacology 2011 25, 211–221.

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