Neurosteroids and potential therapeutics: Focus on pregnenolone

Vallée M(1).

Author information:
(1)INSERM U862, Neurocentre Magendie, Pathophysiology of Addiction, Bordeaux
F33077, France; Université de Bordeaux, Bordeaux F33077, France. Electronic
address: .

Considerable evidence from preclinical and clinical studies shows that steroids
and in particular neurosteroids are important endogenous modulators of several
brain-related functions. In this context, it remains to be elucidated whether
neurosteroids may serve as biomarkers in the diagnosis of disorders and might
have therapeutic potential for the treatment of these disorders. Pregnenolone
(PREG) is the main steroid synthesized from cholesterol in mammals and
invertebrates. PREG has three main sources of synthesis, the gonads, adrenal
glands and brain and is submitted to various metabolizing pathways which are
modulated depending on various factors including species, steroidogenic tissues
and steroidogenic enzymes. Looking at the whole picture of steroids, PREG is
often known as the precursor to other steroids and not as an active steroid per
se. Actually, physiological and brain functions have been studied mainly for
steroids that are very active either binding to specific intracellular
receptors, or modulating with high affinity the abundant membrane receptors,
GABAA or NMDA receptors. However, when high sensitive and specific
methodological approaches were available to analyze low concentrations of
steroids and then match endogenous levels of different steroid metabolomes,
several studies have reported more significant alterations in PREG than in other
steroids in extraphysiological or pathological conditions, suggesting that PREG
could play a functional role as well. Additionally, several molecular targets of
PREG were revealed in the mammalian brain and beneficial effects of PREG have
been demonstrated in preclinical and clinical studies. On this basis, this
review will be divided into three parts. The first provides a brief overview of
the molecular targets of PREG and the pharmacological effects observed in animal
and human studies. The second will focus on the possible functional role of PREG
with an outline of the modulation of PREG levels in animal and in human
research. Finally, the review will highlight the possible therapeutic uses of
PREG that point towards the development of pregnenolone-like molecules.

Copyright © 2015 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.jsbmb.2015.09.030
PMID: 26433186 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus