Overview of the Molecular Steps in Steroidogenesis of the GABAergic Neurosteroids Allopregnanolone and Pregnanolone

Abstract

Allopregnanolone and pregnanolone-neurosteroids synthesized from progesterone in the brain, adrenal gland, ovary and testis-have been implicated in a range of neuropsychiatric conditions including seizure disorders, post-traumatic stress disorder, major depression, post-partum depression, pre-menstrual dysphoric disorder, chronic pain, Parkinson's disease, Alzheimer's disease, neurotrauma, and stroke. Allopregnanolone and pregnanolone equipotently facilitate the effects of gamma-amino-butyric acid (GABA) at GABA A receptors, and when sulfated, antagonize N-methyl-D-aspartate receptors. They play myriad roles in neurophysiological homeostasis and adaptation to stress while exerting anxiolytic, antidepressant, anti-nociceptive, anticonvulsant, anti-inflammatory, sleep promoting, memory stabilizing, neuroprotective, pro-myelinating, and neurogenic effects. Given that these neurosteroids are synthesized de novo on demand, this review details the molecular steps involved in the biochemical conversion of cholesterol to allopregnanolone and pregnanolone within steroidogenic cells. Although much is known about the early steps in neurosteroidogenesis, less is known about transcriptional, translational, and post-translational processes in allopregnanolone-and pregnanolone-specific synthesis. Further research to elucidate these mechanisms as well as to optimize the timing and dose of interventions aimed at altering the synthesis or levels of these neurosteroids is much needed. This should include the development of novel therapeutics for the many neuropsychiatric conditions to which dysregulation of these neurosteroids contributes.

Metabolomics of sebum reveals lipid dysregulation in Parkinson’s disease

“…Due to their bioactive role within cell membranes sphingolipids are strongly linked to sterol metabolism pathways, and have an established role in the modulation of steroidogenesis. There is a direct link between ceramides and the biosynthesis of cholesterol which is then the feed in substrate for steroid hormone biosynthesis, the most significantly altered pathway shown for medicated PD patients 49 , 50 .…”

BV-2 Microglial Cells Respond to Rotenone Toxic Insult by Modifying Pregnenolone, 5α-Dihydroprogesterone and Pregnanolone Levels

“…Allopregnanolone and pregnanolone equipotently and positively modulate the action of GABA at GABA A synaptic and extrasynaptic receptors. At nanomolar doses, these stereoisomers increase the effects of GABA on GABA A receptor-mediated chloride ion influx 7 to 10 times, thus markedly improving the inhibitory impact of GABA on neuronal firing [ 21 , 52 ]. In contrast, sulfated, allopregnanolone, and pregnanolone potently antagonize N-methyl-D-aspartate (NMDA) receptors [ 52 ].…”

“…At nanomolar doses, these stereoisomers increase the effects of GABA on GABA A receptor-mediated chloride ion influx 7 to 10 times, thus markedly improving the inhibitory impact of GABA on neuronal firing [21,52]. In contrast, sulfated, allopregnanolone, and pregnanolone potently antagonize N-methyl-D-aspartate (NMDA) receptors [52]. However, allopregnanolone can activate gene transcription via PR after being converted back to 5α-DHP.…”

The Role of HPA Axis and Allopregnanolone on the Neurobiology of Major Depressive Disorders and PTSD

“…It is worth highlighting that pregnanolone—the equipotent isomer of allopregnanolone—is also synthesized from progesterone through the action of the 5β-reductase (5β-R) enzyme, which originates 5β-dihydroprogesterone (5β-DHP). 5β-DHP is also transformed by 3α-HSD into pregnanolone [ 34 , 35 ].…”