allopregnanolone

Allopregnanolone, also known as 3α-hydroxy-5α-pregnan-20-one, is a neuroactive steroid derived from progesterone. It is produced endogenously in the brain and other tissues through the action of 5α-reductase and 3α-hydroxysteroid dehydrogenase, which convert progesterone to 5α-dihydroprogesterone and then to allopregnanolone. It exists as a rapidly acting modulator of neuronal function.

Mechanism of action: Allopregnanolone is a potent positive allosteric modulator of GABA type A receptors, with particular potency at extrasynaptic δ-subunit-containing receptors. By enhancing GABAergic inhibition, it produces sedative, anxiolytic, anticonvulsant, and neuroprotective effects. It can also influence other neurotransmitter systems and stress responses.

Physiological and clinical relevance: Endogenously, allopregnanolone levels fluctuate with reproductive hormones, rising during pregnancy and declining postpartum. Clinically, it has been explored as a therapeutic agent for postpartum depression and other mood disorders. Brexanolone, a synthetic formulation of allopregnanolone, was approved by the U.S. FDA in 2019 for postpartum depression and is administered by continuous IV infusion under medical supervision for about 60 hours. Its administration can cause sedation and respiratory depression, especially when used with other central nervous system depressants.

Synthesis and research: Allopregnanolone is biosynthesized from progesterone via 5α-reductase and 3α-hydroxysteroid dehydrogenase. Endogenous levels are measured in central nervous system and peripheral tissues. Beyond mood disorders, allopregnanolone is studied for potential roles in epilepsy, neuroprotection after brain injury, and stress-related conditions, with ongoing research into safety and pharmacokinetics of exogenous administration.