Elsevier

Psychoneuroendocrinology

Volume 23, Issue 8, November 1998, Pages 963-987
Psychoneuroendocrinology

NEUROSTEROIDS: A NOVEL FUNCTION OF THE BRAIN

https://doi.org/10.1016/S0306-4530(98)00071-7Get rights and content

Abstract

Neurosteroids are synthetized in the central and peripheral nervous system, particularly but not exclusively in myelinating glial cells, from cholesterol or steroidal precursors imported from peripheral sources. They include 3-hydroxy-Δ5-compounds, such as pregnenolone (PREG) and dehydroepiandrosterone (DHEA), their sulfates, and reduced metabolites such as the tetrahydroderivative of progesterone 3α-hydroxy-5α-pregnane-20-one (3α,5α-TH PROG). These compounds can act as allosteric modulators of neurotransmitter receptors, such as GABAA, NMDA and sigma receptors. Progesterone (PROG) is also a neurosteroid, and a progesterone receptor (PROG-R) has been identified in peripheral and central glial cells. At different places in the brain, neurosteroid concentrations vary according to environmental and behavioral circumstances, such as stress, sex recognition and aggressiveness. A physiological function of neurosteroids in the central nervous system is strongly suggested by the role of hippocampal PREGS with respect to memory, observed in aging rats. In the peripheral nervous system, a role for PROG synthesized in Schwann cells has been demonstrated in the repair of myelin after cryolesion of the sciatic nerve in vivo and in cultures of dorsal root ganglia neurites. It may be important to study the effect of abnormal neurosteroid concentrations/metabolism with a view to the possible treatment of functional and trophic disturbances of the nervous system. © 1998 Elsevier Science Ltd. All rights reserved.

Section snippets

NEUROSTEROIDS: THE BEGINNING

The work to describe the synthesis and metabolic pathways of neurosteroids, and establish their physiological and pathological function and mechanism(s) of action has encountered some major difficulties: (1) We (see acknowledgements) met many analytical problems, qualitative and quantitative because of the low concentration and the lipoı̈dal nature of neurosteroids, which have to be separated from the highly lipidic constituents of neural tissues. Strictly controlled conditions had to be

BIOSYNTHESIS AND METABOLISM OF NEUROSTEROIDS

3β-hydroxy-Δ5-steroids PREG and DHEA are, in steroidogenic glands, intermediary compounds between cholesterol and active 3-oxo-Δ4-steroids such as PROG and testosterone.

Cholesterol itself can be synthesized in many cells of the nervous system from low molecular weight precursors (for example mevalonate→cholesterol, PREG and metabolites in cultured glial cells (Hu et al., 1989, Jung-Testas et al., 1989, Jurevics and Morell, 1995). There is also evidence for lipoprotein receptors favoring

RECEPTORS OF NEUROSTEROIDS

To the diversity of neurosteroids themselves should be added that of the receptor systems.

Behaviour

We observed an increase of brain DHEAS related to surgical (adrenalectomy and gonadectomy) stress conditions in the rats (Corpéchot et al., 1981).

We also observed that the exposure of male rats to females (Fig. 8) leads to a decrease of PREG in the rat olfactory bulb, an effect apparently due to a pheromonal stimulus, ovarian-dependent in the females, and testosterone-dependent in males (orchiectomy suppresses the response and testosterone reestablishes it) (Corpéchot et al., 1985).

A particular

CONCLUSIONS

Neurosteroids are synthesized in the central and peripheral nervous system, particularly in myelinating glial cells, but also in astrocytes and many neurons, and act in the nervous system. Synthetic pathways may start from cholesterol or from steroidal precursor(s) imported from peripheral sources. Measured concentrations of neurosteroids are consistent with the affinities of receptor systems with which they interact in the nervous system. Both intracellular and membrane receptors responding to

Acknowledgements

I would like to thank researchers and students of my laboratory, and colleagues from many others institutions who helped us to collect the data reported in this presentation. When I say ‘we’ in the text, it means first of all P. Robel and his wise and persistent contributions, and for many years C. Corpéchot, I. Jung-Testas, B. Eychenne, M. El-Etr, C. Le Goascogne and more recently Y. Akwa, K. Rajkowski, M. Schumacher. The work of my laboratory has been supported mainly by INSERM. I gratefully

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