Boero, G., Porcu, P., & Morrow, A. L. (2020). Pleiotropic actions of allopregnanolone underlie therapeutic benefits in stress-related disease. Neurobiology of stress, 12, 100203. https://doi.org/10.1016/j.ynstr.2019.100203
Boero G, Porcu P, Morrow AL. Pleiotropic actions of allopregnanolone underlie therapeutic benefits in stress-related disease. Neurobiology of stress. 2020;12:100203. doi:10.1016/j.ynstr.2019.100203
Boero, Giorgia, et al. "Pleiotropic actions of allopregnanolone underlie therapeutic benefits in stress-related disease." Neurobiology of stress, vol. 12, 2020, pp. 100203.
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University of North Carolina at Chapel Hill0130frc33
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RRM Academy Synopsis
Allopregnanolone acts on three stress pathways, a review argues
A 2020 narrative review of animal and early human studies argues that allopregnanolone, a steroid made from progesterone, acts on three stress pathways at once. The authors say this may help in PTSD, depression, alcohol use disorders and seizures.
Key Findings
The authors name three targets: GABAA receptors (restoring GABA-mediated inhibition), corticotropin releasing factor (CRF) signaling, and inflammatory signaling through Toll-like receptors (TLRs) in immune cells and brain.
In socially isolated male rats, allopregnanolone prevented or normalized the abnormal stress hormone response and the depression- and anxiety-like behavior.
In cultured mouse macrophage cells, allopregnanolone and pregnenolone completely inhibited the TLR4 inflammatory markers that lipopolysaccharide raised.
Women with moderate to severe postpartum depression improved quickly on Brexanolone, an allopregnanolone formulation, and the effect lasted more than a month. A trial in super refractory status epilepticus showed no improvement.
Among 92 veterans, 4 weeks of pregnenolone eased chronic pain symptoms by 20%, compared with 4% in the placebo group.
Interpretation
This narrative review joins rodent experiments, cell studies, case reports and early human trials into one framework. Many animal findings come from male rats and mice. The main human evidence is Brexanolone in postpartum depression, and the authors say it is unknown whether its benefit depends on GABAergic action, which they consider likely to contribute. The three-pathway idea is the authors' hypothesis. They call for clinical studies of allopregnanolone and its precursors.
RRM Context
Ovulation makes progesterone, and the body turns it into allopregnanolone. The authors report that progesterone inhibits inflammatory signaling after brain injury in rats. RRM treats a healthy ovulatory cycle as a source of this hormone.
Our editorial summary of this paper, not the article's abstract.
Abstract
For several years, research from around the world has suggested that the neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone) may have therapeutic potential for treatment of various stress-related diseases including post-traumatic stress disorder (PTSD), depression, alcohol use disorders (AUDs), as well as neurological and psychiatric conditions that are worsened in the presence of stress, such as multiple sclerosis, schizophrenia, and seizure disorders. In this review, we make the argument that the pleiotropic actions of allopregnanolone account for its ability to promote recovery in such a wide variety of illnesses. Likewise, the allopregnanolone precursors, pregnenolone and progesterone, share many actions of allopregnanolone. Of course, pregnenolone and progesterone lack direct effects on GABAA receptors, but these compounds are converted to allopregnanolone in vivo. This review presents a theoretical framework for understanding how endogenous neurosteroids that regulate 1) γ-aminobutyric acid (GABA)A receptors, 2) corticotropin releasing factor (CRF) and 3) pro-inflammatory signaling in the innate immune system and brain could play a key role in both the prevention and treatment of stress-related disease. We further discuss cautions and limitations of allopregnanolone or precursor therapy as well as the need for more clinical studies.
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