Allopregnanolone

Allopregnanolone is a selective activator of GABA-A receptor with the concentration of 10 nM [1].
GABA-A receptor is a pentameric transmembrane receptor and sits in the membrane of neuron. As a subtype of receptor for the neurotransmitter GABA, GABA-A receptor mediates the bulk of synaptic inhibition in the central nervous system and prevents action potential generation by short-circuiting the depolarization produced by excitatory neurotransmission. It has been shown that allopregnanolone can directly activate GABA-A receptor and it also can allosteric enhance GABA-evoked currents to function [2] [1].
Allopregnanolone is an agonist for GABA-A receptor. When tested with rat retinas exposed to hydrostatic pressure (75 mm Hg) for 24 hours, administration of alloprenanolone significantly suppressed pressure-induced axonal swelling via functioning on GABA-A R in a dose-dependent manner [1].
In spinal cord slides from naïve rats, pre-incubation with TGOT significantly lower the following allopregnanolone (0.11 ± 0.04 ng/mg) treatment thus decayed GABA-A R which resulted in the spinal neurosteroidogenesis [3].
It is also reported that subcutaneously injected allopregnanolone to male Wistar rats once daily over five consecutive days resulted in energy intake and weight gain increasement [4].
References:
[1].    Ishikawa, M., et al., Neurosteroids are endogenous neuroprotectants in an ex vivo glaucoma model. Invest Ophthalmol Vis Sci, 2014. 55(12): p. 8531-41.
[2].    Maguire, J. and I. Mody, Steroid hormone fluctuations and GABA(A)R plasticity. Psychoneuroendocrinology, 2009. 34 Suppl 1: p. S84-90.
[3].    Juif, P.E., et al., Long-lasting spinal oxytocin analgesia is ensured by the stimulation of allopregnanolone synthesis which potentiates GABA(A) receptor-mediated synaptic inhibition. J Neurosci, 2013. 33(42): p. 16617-26.
[4].    Holmberg, E., et al., Repeated allopregnanolone exposure induces weight gain in schedule fed rats on high fat diet. Physiol Behav, 2015. 140: p. 1-7.

The relationship between weight gain during pregnancy and allopregnanolone levels: a longitudinal study.[Pubmed:28381564]

Endocr Connect. 2017 May;6(4):253-259.

OBJECTIVE: Large weight gain during pregnancy is a risk factor for complications for mother and fetus. Hunger and satiety are regulated in the hypothalamus, where the gamma-amino-butyric acid system (GABA) has an important role. Allopregnanolone, a progesterone metabolite, increases during pregnancy and is a potent GABA-A receptor modulating steroid. Allopregnanolone has been shown to induce overeating in rodents. The aim was to investigate whether there is a relationship between weight gain and Allopregnanolone concentrations during pregnancy in humans. DESIGN: A longitudinal, cohort study. METHODS: Pregnant women (n = 56) were recruited in primary care in northern Sweden. Allopregnanolone concentrations in plasma were measured using radioimmunoassay and weight was measured in gestational weeks 12 and 35. RESULTS: Weight increase correlated significantly to Allopregnanolone in late pregnancy increase (rs = 0.320; P = 0.016), indicating a positive relationship between weight increase and Allopregnanolone increase. A positive relationship was also noted between Allopregnanolone in the 35th gestational week and weight increase. Women who gained >/=11 kg during pregnancy showed higher Allopregnanolone concentrations in week 35 and higher increase compared to women who increased <11 kg (P = 0.006 and P = 0.009 resp.). There was no difference in weight or Allopregnanolone concentrations at the onset of pregnancy. CONCLUSIONS: The results show a relationship between weight gain during pregnancy and increase in Allopregnanolone concentrations.

Lower allopregnanolone during pregnancy predicts postpartum depression: An exploratory study.[Pubmed:28278440]

Psychoneuroendocrinology. 2017 May;79:116-121.

Current evidence is mixed on the role of progesterone and its metabolites in perinatal mood and anxiety disorders. We measured second and third trimester (T2 and T3) progesterone (PROG) and Allopregnanolone (ALLO) levels by ELISA and postpartum depression (PPD) by clinician interview (DSM-IV criteria) in 60 pregnant women with a prior diagnosis of a mood disorder. Methods included multivariate and logistic regression with general linear mixed effect models. We found that, after adjustment, every additional ng/mL of T2 ALLO resulted in a 63% (95% CI 13% to 84%, p=0.022) reduction in the risk of developing PPD. Our findings extend previous work connecting ALLO and depression within pregnancy, and indicate that the relationship between pregnancy ALLO and PPD is worth further exploration in a larger sample.

Respiratory responses to progesterone and allopregnanolone following chronic caffeine treatment in newborn female rats.[Pubmed:28232221]

Respir Physiol Neurobiol. 2017 Jun;240:32-40.

We recently showed that in 12-day-old male rats exposed to caffeine for 10 consecutive days, progesterone inhibits the respiratory response to hypoxia and increases apnea frequency (Uppari et al., 2016). This was partly due to a higher inhibitory response of GABAa receptor to Allopregnanolone, the neuroactive metabolite of progesterone. In the present study, we addressed whether similar effects occur in females. We used newborn female rats daily gavaged with water (control) or caffeine (15mg/kg) between the postnatal (P) days 3-12. At P12, we recorded ventilation, metabolic rate, and apnea frequency and duration in normoxia and in response to moderate hypoxia, following an intraperitonial injection of progesterone (4mg/kg) or Allopregnanolone (10mg/kg). In control rats, progesterone had no effect on breathing in normoxia and in hypoxia, and in rats treated with caffeine it decreased the initial increase in respiratory frequency in hypoxia. In both groups, allopregnalone decreased breathing frequency in normoxia and in hypoxia and increased the frequency of apnea in normoxia in control rats and in rats treated with caffeine. Injection of bicuculline (a specific GABAa receptor antagonist) prevented the inhibitory effects of Allopregnanolone on breathing in both groups. These data indicate that chronic caffeine treatment unmasked an inhibitory effect of progesterone on the hypoxic response but this was weaker than in males, and contrasting to what was observed in male rats (Uppari et al., 2016), GABAa receptors are not significantly affected by chronic caffeine treatment in newborn female rats.

LC-MS/MS simultaneous analysis of allopregnanolone, epiallopregnanolone, pregnanolone, dehydroepiandrosterone and dehydroepiandrosterone 3-sulfate in human plasma.[Pubmed:28207286]

Bioanalysis. 2017 Mar;9(6):527-539.

AIM: Several neuropsychopharmacological properties have been attributed to the 3alpha-reduced pregnane steroids, Allopregnanolone and pregnanolone, as well as to dehydroepiandrosterone sulfate because of their ability to modulate gamma-aminobutyric acid (GABAA) receptors in the CNS. In order to understand better their role in several mechanisms in CNS, a new methodology is proposed to monitor these compounds in human plasma. Methodology & results: The analytes were first derivatized with 2-hydrazinopyridine and extracted from plasma using SPE. Then, the compounds were separated and detected by LC-MS/MS. A mobile phase of formic acid (0.1%) in water and methanol through a gradient of composition and a flow rate of 0.3 ml min(-1) resulted in good separations of the analytes. Linear responses in wide range of concentrations and LOQs ranging from 10 (dehydroepiandrosterone 3-sulfate) to 40 pg ml(-1) (dehydroepiandrosterone) were obtained in <9 min. The method proposed has been validated and then applied to monitor these neurosteroids in plasma samples from ten volunteers. CONCLUSION: For the first time, a straightforward and reliable method for the chromatographic separation of Allopregnanolone, epiAllopregnanolone and pregnanolone, as well as of dehydroepiandrosterone and dehydroepiandrosterone 3-sulfate was carried out, with optimal accuracy, sensitivity and specificity.

Neurosteroids: endogenous regulators of the GABA(A) receptor.[Pubmed:15959466]

Nat Rev Neurosci. 2005 Jul;6(7):565-75.

GABA(A) (gamma-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs. Certain naturally occurring pregnane steroids can potently and specifically enhance GABA(A) receptor function in a nongenomic (direct) manner, and consequently have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic properties. These steroids not only act as remote endocrine messengers, but also can be synthesized in the brain, where they modify neuronal activity locally by modulating GABA(A) receptor function. Such 'neurosteroids' can influence mood and behaviour in various physiological and pathophysiological situations, and might contribute to the behavioural effects of psychoactive drugs.

Neurosteroids act on recombinant human GABAA receptors.[Pubmed:2160838]

Neuron. 1990 May;4(5):759-65.

The endogenous steroid metabolites 3 alpha,21dihydroxy-5 alpha-pregnan-20-one and 3 alpha-hydroxy-5 alpha-pregnan-20-one potentiate GABA-activated Cl- currents recorded from a human cell line transfected with the beta 1, alpha 1 beta 1, and alpha 1 beta 1 gamma 2 combinations of human GABAA receptor subunits. These steroids are active at nanomolar concentrations in potentiating GABA-activated Cl- currents and directly elicit bicuculline-sensitive Cl- currents when applied at micromolar concentrations. The potentiating and direct actions of both steroids were expressed with every combination of subunits tested. However, an examination of single-channel currents recorded from outside-out patches excised from these transfected cells suggests that despite the common minimal structural requirements for expressing steroid and barbiturate actions, the mechanism of GABAA receptor modulation by these pregnane steroids may differ from that of barbiturates.