NEUROSTEROIDS: A NOVEL FUNCTION OF THE BRAIN
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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