Recent developments in the significance and therapeutic relevance of neuroactive steroids — Introduction to the special issue

Abstract

The special issue heralds an exciting time in the field when the significance of neuroactive steroids in the regulation of inhibitory transmission is being realized and translated to new treatments for intractable neurologic and psychiatric conditions. In the past year, the binding sites for neuroactive steroids on γ-aminobutyric acid type A (GABA A ) receptors have been discovered and clinical trials for epilepsy and traumatic brain injury have been successful. New data in animal models points to the potential value of neuroactive steroids in other central nervous system (CNS) disorders including depression, schizophrenia, alcoholism, multiple sclerosis and other neurodegenerative conditions. How can one class of compounds have so many potential applications? The answer may lie in the ability of neuroactive steroids to regulate synaptic and extrasynaptic inhibitory transmission across brain, hypothalamic-pituitary-adrenal (HPA) axis function, inflammatory processes and myelin formation. The manuscripts in this issue of Pharmacology and Therapeutics will bring you up to date on the sites of neurosteroid actions, the systemic and molecular consequences of these actions and the potential therapeutic relevance of neuroactive steroid effects for CNS disease. These studies point to the opportunity for more translational research into potential therapeutic applications and evaluation of potential untoward side effects following long-term treatment.

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

“…Both 3a,5a-THP and 3a,5a-THDOC enhance neuronal inhibition at binding sites on GABA A receptors (Hosie et al, 2006) and produce behavioral effects similar to those of ethanol. These GABAergic steroids are potent positive modulators of GABA A receptors, producing pharmacological effects in nanomolar concentrations (Morrow et al, 1987), and studies suggest that modulating GABAergic steroid levels may have therapeutic value for treating multiple psychiatric disorders (Marx et al, 2006;Morrow, 2007;Rasmusson et al, 2006;Strohle et al, 2002;Uzunova et al, 1998).…”

“…Evidence from multiple laboratories suggests that 3a,5a-THP and 3a,5a-THDOC contribute to ethanol's pharmacological effects in rats (Morrow, 2007). Ethanol activates the hypothalamic-pituitary-adrenal (HPA) axis (Rivier et al, 1984;VanDoren et al, 2000), increasing 3a,5a-THP and 3a,5a-THDOC in the blood plasma, cerebral cortex, and hippocampus (Barbaccia et al, 1999;Porcu et al, 2009;VanDoren et al, 2000).…”

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

“…Acute EtOH dynamically regulates local 3a,5a-THP levels in several subcortical regions of adult rats, independent of the adrenal glands [104,105]. Several lines of evidence also suggest that 3a,5a-THP and THDOC contribute to EtOH's pharmacological effects in rats [106]. The levels of these and other neurosteroids change dramatically during embryonic development, parturition, and postnatal development [107][108][109].…”

Allopregnanolone and Pregnanolone Analogues Modified in the C Ring: Synthesis and Activity

“…The 3α-hydroxy group formed was then protected by esterification, and 12 oxo group in benzoate 9 was reduced with sodium borohydride to yield 12β-alcohol 10. The expected 12β-configuration of this compound as well as of other products was confirmed by 1 H NMR spectroscopy (see the Experimental Section).…”

“…Although steroids in general are widely understood as a class of natural products, which hold only little potential of a new breakthrough, neurosteroids are still studied with great interest (see the "Neurosteroid" copy 1,2 of Pharmacol. Ther.…”