Synthetic neurosteroids on brain protection

REY, M.; COIRINI, H.

NEURAL REGENERATION RESEARCH

SHENYANG EDITORIAL DEPT NEURAL REGENERATION RES

Año: 2015 vol. 10 p. 17 - 21

1673-5374

Neurosteroids (NS) are endogenous regulators of neuronal excitability. Inside the brain, reduced progesterone metabolites, like allopregnanolone and pregnanolone, are highly selective and potent modulators of GABAA receptor-mediated neurotransmission. Therefore, their activities as anticonvulsant, anesthetics, anxiolytic and sedative-hypnotic agents results useful for several neurological and psychiatric disorders. Allopregnanolone administration produces neuroprotective effects against adverse early life events and neurogenic effects on neurodegenerative diseases. These progesterones metabolites result useful for therapeutic treatments of different pathologies, reducing the exposure to effects. The principal disadvantages of endogenous NS administration are their rapid metabolism and their low oral bioavailability. Synthetic steroids (SS) analogues or endogenous NS stimulation synthesis might constitute a promising novel strategy for the treatment of several disorders. Several studies indicate that 3a-hydroxyl configuration is the key for binding and activity, but steroid nucleus modifications may emphasize different pharmacophores. Among the SS developed until now are ganaxolone and alphaxalone. They have anesthetic and anticonvulsant properties. On the other hand SS ent-neurosteroids produced more potent TBPS binding inhibition from GABAA receptor than alphaxalone. Moreover we found that some SS epoxies reduce TBPS binding and stimulate flunitrazepam and muscimol binding in a dose-dependent manner. Also, GABAA receptors are involved in anxiolytic effects, and these properties were observed with the synthetic allopregnanolone analogue Co 2-6749. Similar neuroprotective effects of allopregnanolone have been observed with several SS in hypoxia-induced brain injury models, like the SS RU486, triol and ent-steroid of 17β-estradiol. We also found, neuroprotective actions with two SS epoxies in cerebral cortex and hippocampus cultures. Specific enzymes and nuclear hormone receptors for endogenous steroids have structurally defined binding sites. In fact, the SS developed should lack the possibility to bind with high affinity to these proteins. Therefore SS drugs might not strongly interfere with steroids biosynthesis or their specific receptors. It would be also advantageous that the half life of the SS might be quite different and potentially longer, than those of steroid already used as anticonvulsants, anxiolytics, or another neuroactive-neurogenic agents. Thus, it is likely that the development of new SS for therapeutical uses will continue requiring a great deal of effort with the attendant generation of new knowledge.