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. 2020 May 14:11:236.
doi: 10.3389/fendo.2020.00236. eCollection 2020.

Allopregnanolone, the Neuromodulator Turned Therapeutic Agent: Thank You, Next?

Graziano Pinna  1
Affiliations

Allopregnanolone, the Neuromodulator Turned Therapeutic Agent: Thank You, Next?

Graziano Pinna. Front Endocrinol (Lausanne). .

Erratum in

No abstract available

Keywords: 3α-HSD; 5α-reduced steroids; 5α-reductase; GABAA receptor; allopregnanolone (3α,5α-THP); brexanolone; fast-acting antidepressant; postpartum depression.

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Figures

Figure 1
Figure 1
Brexanolone is superior to traditional antidepressants in the treatment of mood disorders. (A) Patients with mood disorders, including major unipolar depression and PTSD, exhibit serum, plasma, CSF, and brain reduction of allopregnanolone levels and/or biosynthesis, which includes the enzymes, 5α-reductase type I (5α-RI), and 3α-hydroxysteroid dehydrogenase (3α-HSD) [(18, 28, 30); reviewed in (10, 42)]. In women with PTSD, progesterone, and the immediate allopregnanolone precursor, 5α-dihydroprogesterone (5α-DHP) levels fail to change and their ratios with allopregnanolone and pregnanolone (allopregnanolone's equipotent GABAergic isomer), concentration in the CSF and plasma points to a possible deficit at the 3α-HSD enzyme expression/function levels (43). Likewise, in PTSD male patients, the CSF allopregnanolone concentrations are decreased for an apparent deficit in 5α-RI expression/function, which negatively correlates with PTSD and depression symptoms (–45). Thus, the concentration and the ratio of allopregnanolone with its parental neuroactive steroids can suggest deficits in their enzymatic pathway, which may unveil biomarkers of sex hormone-related mood disorders. Allopregnanolone's mechanism of action includes activation of mainly extrasynaptically-expressed GABAA receptors. GABAA receptor offers two residues for neurosteroid action; one is located between α and β subunits, and the second is a cavity on α subunits (34). The efficacy of neurosteroids at GABAA receptors is greatly enhanced by the αβδ-containing GABAA receptor subtype, which is characteristic of tonic inhibition mediated by extrasynaptic receptors (21). Allopregnanolone plays a pivotal neurophysiological role by modulating the fine-tuning and strength of GABAA receptors (32). By this mechanism, allopregnanolone appears to regulate emotional behavior and the pharmacological response of GABAA receptor. Altered GABAA receptor subunit composition has been observed in several pathophysiological conditions, including across the menstrual cycle, changes in hormonal shape during pregnancy, as well as during protracted stress (46). Stress, specifically, results in a GABAA receptor composition with increased sensitivity for neurosteroids and neurosteroid-like molecules (e.g., synthetic allopregnanolone analogs) [(29); reviewed in (42)]. These observations are in support of treatments that stimulate allopregnanolone biosynthesis for the therapeutic management of stress-induced psychiatric disorders, for which traditional anxiolytics or antidepressants are ineffective. (B) Brexanolone, a β-cyclodextrin-based parenterally administered soluble formulation of allopregnanolone is marketed as Zulresso™ and it is the first and only specific treatment for postpartum depression. Brexanolone is one of only two recently FDA-approved fast-acting antidepressants. In clinical trials, women with postpartum depression treated with brexanolone improved their symptoms compared with placebo in 2.5 days. Symptoms were measured before and after treatment. Follow-up studies showed that women receiving the treatment maintained the therapeutic gains for at least 30 days (41). Side effects include risk of sedation or loss of consciousness during treatment. For these reasons women who undergo treatment will be monitored by a healthcare professional in a healthcare setting. Other side effects may include sleepiness, dry mouth, flushing of the skin or face. A clinical trial using the orally-active allopregnanolone analog, SAGE 217 has recently failed for non-compliance issues that were noted with about 10% of patients presenting no blood drug levels. However, statistical significance was achieved at days 3, 8, 12, and 15 in patients with measurable drug concentration levels of SAGE-217. Hence, these allopregnanolone derivatives are highly promising in the treatment of mood disorders, from postpartum depression to major depression and, probably, in PTSD, which, as mentioned above, is characterized by low allopregnanolone levels (43, 45). Another approach is to use neurosteroidogenic drugs (38). These agents may selectively elevate allopregnanolone levels by stimulating enzyme activity/expression levels where a deficit emerges thereby improving mood symptoms avoiding a global expression of allopregnanolone levels.
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