Neuroactive steroids and affective disorders
ABSTRACT Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABA(A)) receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety and depression-related behaviour and may contribute to the therapeutical effects of antidepressant drugs. Attenuations of such neuroactive steroids have been observed during major depression and in several anxiety disorders, suggesting a pathophysiological role in such psychiatric conditions. In panic disorder patients a dysequilibrium of neuroactive steroid composition has been observed, which may represent a counterregulatory mechanism against the occurrence of spontaneous panic attacks. Furthermore, alterations of 3alpha-reduced pregnane steroids during major depression were corrected by successful treatment with antidepressant drugs. However in contrast, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition. In addition, changes in neuroactive steroid concentrations after mirtazapine therapy occurred independently from the clinical response, thereby suggesting that changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of antidepressants rather than clinical improvement in general. Nevertheless, the effects of antidepressant pharmacotherapy on the composition of neuroactive steroids may contribute to the alleviation of certain depressive symptoms, such as amelioration of anxiety, inner tension or sleep disturbances. Moreover, first studies investigating the therapeutical effects of dehydroepiandrosterone revealed promising results in the treatment of major depression. In conclusion, neuroactive steroids are important endogenous modulators of depression and anxiety and may provide a basis for development of novel therapeutic agents in the treatment of affective disorders.
- SourceAvailable from: Olga V Egorova
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- "Some steroids (dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate, allopregnanolone, and other pregnane and androstane steroids designated as neurosteroids ) were found to act as allosteric modulators of neurotransmitter receptors to modulate neuronal excitability through direct interaction with the cell surface (Reddy 2003; Eser et al. 2006; Melcangi et al. 2011). "
ABSTRACT: Studies of steroid modifications catalyzed by microbial whole cells represent a well-established research area in white biotechnology. Still, advances over the last decade in genetic and metabolic engineering, whole-cell biocatalysis in non-conventional media, and process monitoring raised research in this field to a new level. This review summarizes the data on microbial steroid conversion obtained since 2003. The key reactions of structural steroid functionalization by microorganisms are highlighted including sterol side-chain degradation, hydroxylation at various positions of the steroid core, and redox reactions. We also describe methods for enhancement of bioprocess productivity, selectivity of target reactions, and application of microbial transformations for production of valuable pharmaceutical ingredients and precursors. Challenges and prospects of whole-cell biocatalysis applications in steroid industry are discussed.Applied Microbiology and Biotechnology 05/2012; 94(6):1423-47. DOI:10.1007/s00253-012-4078-0
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- "However, the neurosteroid metabolite of progesterone, AP (5a-pregnan-3a-ol-20-one), does play a role. Without pregnancy, AP acts on several systems: it has antidepressant actions (Eser et al. 2006), reduces stress responses (Brunton et al. 2009), anxiety (Frye et al. 2009) and neurodegeneration (Djebaili et al. 2004, 2005; Rhodes et al. 2004), and enhances cognition (Frye et al. 2007) and social and reproductive behaviors (Frye and Walf 2002; Frye and Rhodes 2006; Frye et al. 2009). Levels of AP increase greatly in both the circulation and the brain in pregnancy as a result of increased progesterone secretion by the corpora lutea in rats (Concas et al. 1998). "
ABSTRACT: In rats, late pregnancy is associated with suppressed hypothalamo-pituitary-adrenal (HPA) axis responses to a variety of stressful stimuli. The result is reduced corticosterone secretion following stress, which is considered to give some protection to the fetuses from adverse glucocorticoid programming and limits the catabolic effect of corticosterone, hence minimizing maternal energy expenditure. We have used a model of immune challenge in which systemic administration of the cytokine, interleukin-1β (IL-1β), allows study of the mechanisms underlying HPA axis hyporesponsiveness in late pregnancy. Suppressed responsiveness of parvocellular paraventricular nucleus (pPVN) corticotropin-releasing hormone neurons, and hence the HPA axis, following IL-1β in late pregnancy is evidently explained by presynaptic inhibition of noradrenaline release in the pPVN, owing to increased endogenous opioid peptide enkephalin production in brainstem nucleus tractus solitarii neurons. Allopregnanolone, a neurosteroid metabolite of progesterone, signals the pregnancy status of the animal to the brain and stimulates opioid production in the brainstem. In this review, we discuss the supporting evidence for these mechanisms.Stress (Amsterdam, Netherlands) 01/2011; 14(1):6-12. DOI:10.3109/10253890.2010.482628
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- "Finally, Eser et al. (2006) found that steroids modulate neurotransmitter function, "
ABSTRACT: We propose several pathways that could be involved in major depression. According to our proposal, noradrenaline hypoactivity could occur through a strong presynaptic GABAergic inhibition, via GABA(B) receptors, and serotonin hypoactivity through a strong glutaminergic inhibition via subreceptor 5 of the metabotropic glutaminergic receptor. In this sense, it is important to know whether the antagonists of such receptors might be able to improve the symptoms observed in major depression. Some neuropeptides are also altered in such states (corticotropin-releasing hormone, neuropeptide Y, galanin). It is also important to know whether in addition to current antidepressants the administration of neuropeptides and their agonists/antagonists could ameliorate depressive symptoms.The International journal of neuroscience 07/2010; 120(7):455-70. DOI:10.3109/00207454.2010.483651