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. 2019 Jun 11;13:114. doi: 10.3389/fnbeh.2019.00114

Figure 1.

Figure 1

Timeline of allopregnanolone from its discovery to FDA preapproval for the treatment of mood disorders. Beall and Reichstein discovered allopregnanolone in 1938 in the adrenal glandswhere 5α-reductase metabolizes progesterone into 5α-dihydroprogesterone and then the enzyme 3α-hydroxysteroid dehydrogenase produces allopregnanolone (Beall and Reichstein, 1938). In 1981, Baulieu’s team discovered that the brain “acting like a peripheral gland” synthetize allopregnanolone de novo starting from pregnenolone, the precursor of all neurosteroids (Corpéchot et al., 1981). Allopregnanolone’s pharmacological effects following its administration in animal models and humans are mediated by the fast allosteric modulation of the action of GABA at GABAA receptors (Majewska et al., 1986; reviewed in Belelli et al., 2009). The neurophysiological role of allopregnanolone in fine-tuning GABAA receptors to agonists, positive allosteric modulators, and GABAmimetic agents, was unveiled thereafter (Pinna et al., 2000). Allopregnanolone levels were found decreased in mood disorders, including major unipolar depression and PTSD (Romeo et al., 1998; Uzunova et al., 1998; Rasmusson et al., 2006, 2019).An animal model of stress-induced behavioral dysfunction, including fear extinction deficits and aggressive behavior associated with a corticolimbic allopregnanolone biosynthesis downregulation was proposed therein after (Pinna et al., 2008; Pibiri et al., 2008). More recently, phase 3 clinical trials have established the clinical relevance of allopregnanolone in mood disorders (Kanes S. J. et al., 2017; Meltzer-Brody et al., 2018). Intravenous allopregnanolone (brexanolone or SAGE-547) or an orally-active, allopregnanolone’s analog (SAGE-217), showed a rapid and long-lasting remission of post-partum depression and major depressive disorder symptoms, respectively. These successful clinical trials led to the FDA approval of brexanolone for the treatment of post-partum depression in March 2019 and encouraged the possible future clinical use of brexanolone or SAGE-217 for the treatment of mood disorders, including PTSD.