Neurosteroids: mechanistic considerations and clinical prospects

Abstract

Like other classes of treatments described in this issue's section, neuroactive steroids have been studied for decades but have risen as a new class of rapid-acting, durable antidepressants with a distinct mechanism of action from previous antidepressant treatments and from other compounds covered in this issue. Neuroactive steroids are natural derivatives of progesterone but are proving effective as exogenous treatments. The best understood mechanism is that of positive allosteric modulation of GABA_A receptors, where subunit selectivity may promote their profile of action. Mechanistically, there is some reason to think that neuroactive steroids may separate themselves from liabilities of other GABA modulators, although research is ongoing. It is also possible that intracellular targets, including inflammatory pathways, may be relevant to beneficial actions. Strengths and opportunities for further development include exploiting non-GABAergic targets, structural analogs, enzymatic production of natural steroids, precursor loading, and novel formulations. The molecular mechanisms of behavioral effects are not fully understood, but study of brain network states involved in emotional processing demonstrate a robust influence on affective states not evident with at least some other GABAergic drugs including benzodiazepines. Ongoing studies with neuroactive steroids will further elucidate the brain and behavioral effects of these compounds as well as likely underpinnings of disease.

Fig. 1. Sites of neurosteroid interaction with GABA_A receptors.

Allopregnanolone (mesh structure) in the three neurosteroid binding sites (b–d) identified by photolabeling with photolabile NAS analogs. a (center): the six sites identified by photolabeling are grouped into three clusters: inter-subunit sites β3(+)/α1(−) (brown circle, detailed in d), β3 intra-subunit sites (blue circle, detailed in b), and α1 intra-subunit sites (red circle, detailed in c). Residues photolabeled by different analogs are colored red, green, and blue respectively. This figure is reproduced from [75].

Fig. 2. Schematic of non-GABA actions of NAS (yellow steroid structure).

Depicted is a neuron (left) and microglial cell (right). Some targets may be found in multiple cell classes, so the relevant cell type is not known in all cases. See text for details.

Fig. 3. Circuit diagram.

The diagram depicts oscillatory rhythms affected by NAS compounds in brain areas believed to be key to mood.