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

Type 2 diabetes mellitus: from genes to disease.

The development of type 2 diabetes (T2DM) is determined by two factors: genetics and environment. The genetic background of T2DM is undoubtedly heterogeneous. Most patients with T2DM exhibit two different defects: the im...

Effects of olanzapine and paroxetine on phospholipase D activity in the rat brain.

Background: Phospholipase D (PLD) plays a key role in a second messenger system producing phosphatidic acid, mediating, among others, serotonin 5-HT2 receptor activity. The aim of the study was to evaluate a possible eff...

Elimination kinetics of the novel prodrug cinazepam possessing psychotropic activity in mice.

The kinetics of excretion of the novel tranquilizer cinazepam (3-hydroxy-7-bromo-5-(ortho-chlorophenyl)-1,2-dihydro-3H-1,4-benzdiazepin-2-one hemisuccinate (I)) in mice after a single administration and different schemes...

Lipoic acid - biological activity and therapeutic potential.

α-Lipoic acid (LA; 5-(1,2-dithiolan-3-yl)pentanoic acid) was originally isolated from bovine liver by Reed et al. in 1951. LA was once considered a vitamin. Subsequently, it was found that LA is not a vitamin and is synt...

Important role of 3-methoxytyramine in the inhibition of cocaine sensitization by 1-methyl-1,2,3,4-tetrahydroisoquinoline: an in vivo microdialysis study.

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous compound with neuroprotective and antidopaminergic activities. Our previous research has shown that 1MeTIQ prevents morphine addiction and abates the expr...

Download PDF file
  • EP ID EP150152
  • DOI -
  • Views 102
  • 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