Effects of neurosteroids on the human corticotropin-releasing hormone gene.

Journal Title: Pharmacological Reports - Year 2010, Vol 62, Issue 6

Abstract

Increased activity of hypothalamic-pituitary-adrenal (HPA) axis and hypersecretion of corticotropin-releasing hormone (CRH) are known to be important factors in pathogenesis of some stress-related diseases. Some neurosteroids exert anxiolytic and antidepressant effects probably by inhibition of HPA axis activity. The aim of our study was to find out if neurosteroids can directly affect human CRH gene transcription. The effect of allopregnanolone (ALLO), allotetrahydrodeoxycorticosterone (THDOC), pregnenolone (PGL), PGL sulfate (PGL-S), dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) on CRH expression was determined in differentiated Neuro-2A cells stably transfected with plasmid containing a fragment of human CRH promoter (-663 to + 124 bp) linked to the chloramphenicol acetyltransferase (CAT) reporter gene. It was found that PGL (0.3-30 μM), ALLO (1-30 μM) and THDOC (1-30 μM) present in the culture medium for 5 days in the concentration-dependent manner inhibited CRH-CAT activity. These neurosteroids also inhibited forskolin-stimulated CRH gene transcription with similar potency. In contrast, PGL-S, DHEA and DHEA-S in a concentration from 0.01 to 10 μM had no effect on basal and forskolin-stimulated CRH activity. Further experiments revealed that wortmannin (an inhibitor of phosphatidylinositol 3-kinase; PI3-K) at concentrations of 0.01 and 0.02 μM did not change the inhibitory effect of ALLO (3 μM) and PGL (1 μM) on CRH gene transcription. Moreover, ALLO (3 μM) and PGL (1 μM) present in the culture medium for 5 days did not change the amount of active, phosphorylated form of protein kinase B (PKB, Akt) and extracellular signal-regulated kinase (ERK). The obtained results indicate that PGL, ALLO and THDOC inhibited basal and forskolin-induced CRH gene promoter activity in the differentiated Neuro-2A cells and that these effects did not depend on the activation of PI3-K/Akt and ERK-MAPK pathways.

Authors and Affiliations

Bogusława Budziszewska, Anna Zając, Agnieszka Basta-Kaim, Monika Leśkiewicz, Małgorzata Steczkowska, Władysław Lasoń, Marek Kaciński

Keywords

Related Articles

Effect of prior stress on interleukin-1β and HPA axis responses to acute stress.

Interleukin-1β (IL-1β) level is modulated during multiple stress reactions both in brain structures involved in hypothalamic-pituitary-adrenal (HPA) axis regulation and peripheral systems. Multiple distinct stressors ind...

Changes in hippocampal amino acid concentrations after chronic administration of corticosterone.

The effects of acute rise in corticosterone concentration upon the levels of hippocampal glutamate (Glu) are well described. Much less is known about the effect of chronic elevation of glucocorticoids on hippocampal glut...

Estrogen-induced relaxation of the rat tail artery is attenuated in rats with pulmonary hypertension.

The mechanisms involved in the effects of estrogen on arterial smooth muscle contractility are very complex and not fully clarified. Therefore, the aim of this paper was to examine the mechanisms of estrogen-induced rela...

What's the role of topiramate in the management of patients with hyperkinetic movement disorders?

Topiramate (TPM) is an O-alkyl sulfamate derivative of the naturally occurring monosaccharide D-fructose with an epileptic activity. However, it has been suggested that, in addition to its use in epilepsy, TPM could also...

Disparate effects of anti-TNF-α therapies on measures of disease activity and mediators of endothelial damage in ankylosing spondylitis.

Asymmetric dimethylarginine (ADMA) is associated with endothelial injury. Increased ADMA levels are found in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). We set out to assess the ADMA and symmetric dimethyl...

Download PDF file
  • EP ID EP150152
  • DOI -
  • Views 101
  • Downloads 0

How To Cite

Bogusława Budziszewska, Anna Zając, Agnieszka Basta-Kaim, Monika Leśkiewicz, Małgorzata Steczkowska, Władysław Lasoń, Marek Kaciński (2010). Effects of neurosteroids on the human corticotropin-releasing hormone gene.. Pharmacological Reports, 62(6), 1030-1040. https://europub.co.uk/articles/-A-150152