Overview of the Molecular Steps in Steroidogenesis of the GABAergicNeurosteroids Allopregnanolone and Pregnanolone

摘要

Allopregnanolone and pregnanolone—neurosteroids synthesized from progesterone inthe brain, adrenal gland, ovary and testis—have been implicated in a range ofneuropsychiatric conditions including seizure disorders, post-traumatic stressdisorder, major depression, post-partum depression, pre-menstrual dysphoricdisorder, chronic pain, Parkinson’s disease, Alzheimer’s disease, neurotrauma,and stroke. Allopregnanolone and pregnanolone equipotently facilitate theeffects of gamma-amino-butyric acid (GABA) at GABA receptors, andwhen sulfated, antagonize N-methyl-D-aspartate receptors. They play myriad rolesin neurophysiological homeostasis and adaptation to stress while exertinganxiolytic, antidepressant, anti-nociceptive, anticonvulsant, anti-inflammatory,sleep promoting, memory stabilizing, neuroprotective, pro-myelinating, andneurogenic effects. Given that these neurosteroids are synthesized de novo ondemand, this review details the molecular steps involved in the biochemicalconversion of cholesterol to allopregnanolone and pregnanolone withinsteroidogenic cells. Although much is known about the early steps inneurosteroidogenesis, less is known about transcriptional, translational, andpost-translational processes in allopregnanolone- and pregnanolone-specificsynthesis. Further research to elucidate these mechanisms as well as to optimizethe timing and dose of interventions aimed at altering the synthesis or levelsof these neurosteroids is much needed. This should include the development ofnovel therapeutics for the many neuropsychiatric conditions to whichdysregulation of these neurosteroids contributes.