[A role of neurosteroids in the pathogenesis of psychiatric disorders]. / Rol' neirosteroidov v patogeneze psikhicheskikh rasstroistv.

Despite the proven importance of neurosteroids in many physiological processes, their role in the pathogenesis of the most of psychiatric disorders remains relatively understudied. This article reviews the current clinical evidence on the effects of neurosteroids on the formation and treatment of anxiety disorder, depression, bipolar disorder, and schizophrenia. In particular, the article points out the ambivalent nature of the effects of neurosteroids on GABAA- and other receptors. We are especially interested in the anxiolytic and anxiogenic effects of some neurosteroids, the antidepressant effect of allopregnanolone in treating postpartum and other forms of depression, and the nature of short- and long-term mechanisms of antidepressant effects of neurosteroids of different types. The currently unproven hypothesis about the effect of changes in the level of neurosteroids on the course of bipolar disorder is also discussed, with an analysis of the scientific evidence on the development of schizophrenic symptomatology in relation to changing neurosteroid levels in the context of positive and cognitive symptoms.

Placental endocrine function shapes cerebellar development and social behavior.

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO's synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABAAR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.

Fetal Zone Steroids and Estrogen Show Sex Specific Effects on Oligodendrocyte Precursor Cells in Response to Oxidative Damage.

Oxygen causes white matter damage in preterm infants and male sex is a major risk factor for poor neurological outcome, which speculates the role of steroid hormones in sex-based differences. Preterm birth is accompanied by a drop in 17ß-estradiol (E2) and progesterone along with increased levels of fetal zone steroids (FZS). We performed a sex-based analysis on the FZS concentration differences in urine samples collected from preterm and term infants. We show that, in preterm urine samples, the total concentration of FZS, and in particular the 16α-OH-DHEA concentration, is significantly higher in ill female infants as compared to males. Since we previously identified Nup133 as a novel target protein affected by hyperoxia, here we studied the effect of FZS, allopregnanolone (Allo) and E2 on differentiation and Nup133 signaling using mouse-derived primary oligodendrocyte progenitor cells (OPCs). We show that the steroids could reverse the effect of hyperoxia-mediated downregulation of Nup133 in cultured male OPCs. The addition of FZS and E2 protected cells from oxidative stress. However, E2, in presence of 16α-OH-DHEA, showed a negative effect on male cells. These results assert the importance of sex-based differences and their potential implications in preterm stress response.

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

Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the stressful stimulus is no longer present. In addition to corticosteroids (e.g., cortisol), the neurosteroid allopregnanolone (3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one) participates in negative feedback mechanisms that restore homeostasis. Chronic, repeated exposure to stress impairs the responsivity of the HPA axis and dampens allopregnanolone levels, participating in the etiopathology of psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). MDD and PTSD patients present abnormalities in the HPA axis regulation, such as altered cortisol levels or failure to suppress cortisol release in the dexamethasone suppression test. Herein, we review the neurophysiological role of allopregnanolone both as a potent and positive GABAergic neuromodulator but also in its capacity of inhibiting the HPA axis. The allopregnanolone function in the mechanisms that recapitulate stress-induced pathophysiology, including MDD and PTSD, and its potential as both a treatment target and as a biomarker for these disorders is discussed.

Neurosteroid involvement in threatened preterm labour.

Introduction: The neurosteroid allopregnanolone modulates oxytocin expression in the brain, and its effects arise from its action on the GABAA receptor. Whether neurosteroid levels and the function of the GABAA receptor are involved in the risk of preterm labour in pregnant women is unknown. Methods: Pregnant women with (n = 16) or without (n = 20) threatened preterm labour (TPL) in gestational week 33 + 6 days to 37 + 0 days were studied prospectively with procedures including foetal heart rate monitoring, vaginal examination, ultrasound examination and blood tests to determine allopregnanolone, progesterone and oxytocin levels. The GABAA receptor function in both groups was measured with a saccadic eye velocity test (SEVT). Results: Plasma oxytocin levels were higher in the TPL group than in the control group (41.5 vs. 37.0 pmol/L, respectively, p = .021). Although the allopregnanolone and progesterone levels in both groups did not differ, there was a negative association between blood oxytocin and allopregnanolone (as predictor) levels in the TPL group (B: -3.2, 95% confidence interval (CI): -5.5 to -0.9, p = .012). As a predictor of TPL, progesterone was associated with cervix maturity (odds ratio: 1.02, 95% CI: 1.00-1.04, p = .038). SEVT showed that the women in both groups had similar GABAA receptor functions. In both groups, body mass index correlated with peak saccadic eye velocity (r = .34, p = .044) and negatively with allopregnanolone (r = -.41, p = .013). Conclusions: Neurosteroid levels were unchanged in the peripheral blood of women with TPL, despite the increase in available oxytocin. Although the function of the GABAA receptor was unchanged in women with TPL, to ensure reliable results, saccadic eye velocity should be investigated during a challenge test with a GABAA receptor agonist.

The additive effect of allopregnanolone on ghrelin's orexigenic effect in rats.

The progesterone metabolite, allopregnanolone (AlloP), is a GABAA receptor modulating steroid and is known to have orexigenic and pro-obesity effects. The neurobiological mechanisms underpinning these effects are most likely due to enhanced GABAergic signaling in the lateral arcuate nucleus (ARC) and medial paraventricular nucleus (PVN) of the hypothalamus. Inspired by the finding that GABAergic signaling is also important for the orexigenic effects of the circulating hormone, ghrelin, we sought to determine the extent to which AlloP (one of the most potent endogenous GABAA-receptor modulators) operates alongside ghrelin to enhance food intake. Male rats with ad libitum access to standard chow were injected intravenously with AlloP and/or ghrelin, alone or in combination. The intake of the standard chow was greater after AlloP 1 mg/kg together with ghrelin 30 µg/kg than with 30 µg/kg ghrelin alone. Food intake was also increased for the combined treatment of AlloP 0.5 mg/kg + ghrelin 10 µg/kg, AlloP 1 mg/kg + ghrelin 10 µg/kg, and AlloP 0.5 mg/kg + ghrelin 30 µg/kg. There was no significant difference in food intake between the two ghrelin doses or between the two doses of AlloP and the vehicle. In electrophysiological studies, physiologically relevant concentrations of AlloP prolonged the current decay time of spontaneous inhibitory post-synaptic current of dissociated cells of the ARC and PVN. We conclude that AlloP enhances the hyperphagic effect of ghrelin, findings of potential relevance for the hyperphagia associated with the luteal phase of the reproductive cycle.

Role of neurosteroid allopregnanolone on age-related differences in exercise-induced hypoalgesia in rats.

The beneficial effects of physical activity for pain are denominated exercise-induced hypoalgesia (EIH). Here, we examined the age-related change and potential role of the neurosteroid allopregnanolone (ALLO) on EIH in rats. Adult and aged rats were randomly divided into one of three groups; non-exercise control, Low-exercise, and High-exercise. The animals in the Low- and High-exercise groups were subjected to a 10-minute treadmill workout at 40% and 80% maximum oxygen intake intensity, respectively. In the Low-exercise groups, a significant EIH response was observed in aged but not in adult rats. The pre-treatment with ALLO synthesis inhibitor finasteride, but not opioid-receptor antagonist naloxone, inhibited the Low-exercise induced EIH response in aged rats. Furthermore, the Low-exercise increased brain ALLO levels in aged animals compared with controls, which was correlated with the mechanical pain sensitivity. On the other hand, High-exercise could induce EIH response in both adult and aged animals, but it was more effective in adult rats. The pre-treatment with naloxone, but not finasteride, reduced the EIH observed after High-exercise in both adult and aged rats. Our findings demonstrated that effective EIH can be achieved even by mild-intensity exercise in aged animals via an increase of the brain ALLO levels.

In vitro and in vivo evaluation of silk fibroin functionalized with GABA and allopregnanolone for Schwann cell and neuron survival.

AIM: This in vitro and in vivo study reports on silk fibroin (SF) scaffold, functionalized for in situ delivery of GABA and/or allopregnanolone (ALLO), as biomaterial for potential application in tissue engineering and nerve regeneration. MATERIALS & METHODS: We evaluated the feasibility to design 2D scaffolds (films) made of regenerated Bombyx mori SF, functionalized with GABA and/or ALLO to enhance in vitro biological functions, health, survival and growth of Schwann cells and sensitive neurons of the dorsal root ganglia. RESULTS & CONCLUSION: Our 2D-SF film showed an efficient loading and controllable release of drugs promoting nerve regeneration. SF functionalized film may be helpful for the development of bioengineered conduits and, in principle, have great potential for long-gap nerve injury repair.

Is fetal analgesia necessary during prenatal surgery?

Fetal pain and fetal anesthesia are still matter of debate: some authors hypothesize that several intrauterine endocrine neuroinhibitors (ENIn) anesthetize the fetus, keeping it in a constant state of sleep, and making pharmacological fetal anesthesia useless for fetal surgery, while others argue fetal pain is possible and shoud be prevented with fetal anesthesy. AIM: To retrieve evidences about fetal pain, fetal arousability and about the level of sedation induced by the ENIn, in order to assess the necessity of direct fetal anesthesia during prenatal fetal surgery. METHODS: We performed a careful literature review (1990-2016) on fetal arousability, and on the possibility that ENIn at the average fetal blood levels induce actual anesthesia. We retrieved the papers that fulfilled the research criteria, with particular attention to the second half of pregnancy, the period when most fetal surgery is performed. RESULTS: Fetuses are awake about 10% of the total time in the last gestational weeks, and they can be aroused by external stimuli. ENIn have not an anesthetic effect at normal fetal values, but only when they areartificialy injected at high doses; their blood levels in the last trimester of average pregnancies are not dissimilar either in the fetus or in the mother. CONCLUSIONS: During the second half of the pregnancy, external stimuli can awake the fetuses, although they spend most of the time in sleeping state; the presence of ENIn is absolutely not enough to guarantee an effective anesthesia during surgery. Thus, direct fetal analgesia/anesthesia is mandatory, though further studies on its possible drawbacks are necessary.

Neuroactive steroids and PTSD treatment.

This review highlights early efforts to translate pre-clinical and clinical findings regarding the role of neuroactive steroids in stress adaptation and PTSD into new therapeutics for PTSD. Numerous studies have demonstrated PTSD-related alterations in resting levels or the reactivity of neuroactive steroids and their targets. These studies also have demonstrated substantial variability in the dysfunction of specific neuroactive steroid systems among PTSD subpopulations. These variabilities have been related to the developmental timing of trauma, severity and type of trauma, genetic background, sex, reproductive state, lifestyle influences such as substance use and exercise, and the presence of comorbid conditions such as depression and chronic pain. Nevertheless, large naturalistic studies and a small placebo-controlled interventional study have revealed generally positive effects of glucocorticoid administration in preventing PTSD after trauma, possibly mediated by glucocorticoid receptor-mediated effects on other targets that impact PTSD risk, including other neuroactive steroid systems. In addition, clinical and preclinical studies show that administration of glucocorticoids, 17ß-estradiol, and GABAergic neuroactive steroids or agents that enhance their synthesis can facilitate extinction and extinction retention, depending on dose and timing of dose in relation to these complex PTSD-relevant recovery processes. This suggests that clinical trials designed to test neuroactive steroid therapeutics in PTSD may benefit from such considerations; typical continuous dosing regimens may not be optimal. In addition, validated and clinically accessible methods for identifying specific neuroactive steroid system abnormalities at the individual level are needed to optimize both clinical trial design and precision medicine based treatment targeting.