Studies on the neuroactive steroids

Marie Bicikova, Lucie Sosvorova, Martin Hill, Ludmila Macova, Richard Hampl, Luboslav Starka. Institute of Endocrinology, Prague, 116 94, Czech Republic

Neuroactive steroids (NAS) have rapid, non-genomic actions in CNS. Changed neurosteroid levels are involved in many pathological processes. Regulation of their metabolism and understanding of the mechanism of their actions will help to use them therapeutically.

The effects of these steroids are mediated mainly by modulation of ionotropic receptors of γ-aminobutyric acid (GABAA) or N-methyl-D-aspartate (NMDA) and so influencing influx of Cl- or Ca2+ ions into the cells, resp. Among the best studied NAS belongs reduced progesterone derivative allopregnanolone – a positive modulator of GABAA receptors, with effects similar to those of benzodiazepines. On the other side there are actually often studied or used dehydroepiadrosterone (DHEA) or its sulphate with their negative or positive modulation of GABA or NMDA receptors, respectively.

In this work we summarize our up to now results with plasma or cerebrospinal fluid levels of NAS in several neurological or neuropsychiatric diseases. Until now we have studied neurosteroid levels in women suffering from premenstrual syndrome, catamenial epilepsy or mixed anxiety-depressive disorder. In both sexes we studied neurosteroid levels in neurodegenerative diseases such as: Alzheimer disease and vascular dementia. Recently we reported our findings concerning steroid metabolome in schizophrenic patients. Our results indicate that abnormal levels of DHEA and its 7-hydroxylated metabolites may play a negative role in neurodegenerative diseases. Our new studies are concentrated on the possible role of NAS in CSF of patients with hydrocephalus, enabling prediction and consequent targeted treatment of dementia, which, after initiatory relief, appears in most of the patients (in ½ as early after 3 months-, and in almost ¾ after 3 years from operation). In the hydrocephalus complications we suppose the crucial role of enzyme 11β−hydroxysteroid dehydrogenase (11β−HSD) which is responsible not only for oxido-reductive transformations of glucocorticoids but also for metabolism of above named DHEA and its 7-hydroxylated metabolites.

The later steroids act as regulators of local cortisol activity due to their competition in the cortisol-cortisone balance mediated by 11β−HSD. 7-Hydroxy-dehydroepiandrosterone is marketed as anti-obesity dietary supplement, though no clinical has appeared until now. The aim of our most recent project is to contribute to the discovery of new hormonal factors involved in the formation and development of obesity in children. The results of our study could lead to a new therapeutic approach to the childhood obesity which is a worldwide problem.

The work is supported by the grant No. NT 13542-3 of the Ministry of Health, Czech Republic.