Allopregnanolone: An overview on its synthesis and effects

Abstract

Allopregnanolone, a 3α,5α‐progesterone metabolite, acts as a potent allosteric modulator of the γ‐aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and pathological conditions. In addition, its physiological and neuroprotective effects are also reported. Interestingly, the levels of this neuroactive steroid, as well as its effects, are sex‐dimorphic, suggesting a possible gender medicine based on this neuroactive steroid for neurological disorders. However, allopregnanolone presents low bioavailability and extensive hepatic metabolism, limiting its use as a drug. Therefore, synthetic analogues or a different therapeutic strategy able to increase allopregnanolone levels have been proposed to overcome any pharmacokinetic issues.

Relating neurosteroid modulation of inhibitory neurotransmission to behaviour

“…A variety of mood disorders are associated with, or accompanied by, perturbed levels of the GABAergic neurosteroids such as allopregnanolone 18 . Many animal models have focussed on investigating the consequences of exposure to chronic stress as a vulnerability factor 79 .…”

“…A variety of mood disorders are associated with, or accompanied by, perturbed levels of the GABAergic neurosteroids such as allopregnanolone. 18 Many animal models have focussed on investigating the consequences of exposure to chronic stress as a vulnerability factor. 79 Acute stress in rodents induces an increase in the levels of GABAergic neurosteroids, whereas exposure to chronic stress produces a decrease.…”

“…In this scenario, it was proposed that these steroids would cross the blood–brain barrier and act as endocrine messengers to influence neural inhibition. However, subsequently, it was demonstrated that the enzymes required for synthesis of these pregnane steroids, derived either from cholesterol or from peripheral precursors such as progesterone, are expressed within certain neurones and glial cells in the CNS 15–18 . Therefore, in addition to peripheral endocrine sources of the steroid, neurosteroids synthesised locally in the CNS could potentially act in a paracrine or autocrine manner to influence neuronal signalling 12,15 .…”

“…However, subsequently, it was demonstrated that the enzymes required for synthesis of these pregnane steroids, derived either from cholesterol or from peripheral precursors such as progesterone, are expressed within certain neurones and glial cells in the CNS. [15][16][17][18] Therefore, in addition to peripheral endocrine sources of the steroid, neurosteroids synthesised locally in the CNS could potentially act in a paracrine or autocrine manner to influence neuronal signalling. 12,15 It soon became evident that the endogenous levels of these steroids are not static but change dynamically under a variety of physiological conditions, including during development, puberty and stress, during the ovarian cycle and in pregnancy.…”

Neuroactive steroids: From basic research to clinical use

“…The history of the discovery of allopregnanolone and its synthesis was reported in the review by Diviccaro et al 4 They discussed its role in physiological, neuroprotective and pathological conditions, highlighting the fact that the levels of this neuroactive steroid, as well as its effects, are sexually dimorphic, suggesting the possibility of gender differences for its use in neurological disorders. However, allopregnanolone has a short half‐life in vivo, limiting its use as a drug.…”