Effects of acute progesterone administration upon responses to acute psychosocial stress in men.

Animal studies suggest that neuroactive steroids, in particular progesterone and its metabolites, have stress-dampening effects. However, few studies have explored these effects in humans. In this study, we investigated the effects of acute progesterone administration on responses to the Trier Social Stress Test (TSST). Healthy men participated in the TSST 3.5 hrs after intramuscular injection of 0, 50, or 100 mg progesterone (N = 16, 14, and 14). We measured cardiovascular (heart rate, blood pressure), hormonal (plasma adrenocorticotrophic hormone, cortisol, and noradrenaline), and subjective (e.g., anxiety, arousal) responses to stress in the three groups. Before the TSST, progesterone injections increased plasma levels without altering physiological or subjective states. Stress produced its expected physiological and subjective effects among placebo-treated individuals. Progesterone 50 mg attenuated peak increases in plasma cortisol and reduced changes in negative mood and alertness after stress, yet it increased plasma noradrenaline and systolic blood pressure. Progesterone 100 mg also attenuated stress-induced increases in alertness and arousal, yet it potentiated stress-induced increases in diastolic pressure. Thus, progesterone dampened some of the psychological effects of stress but produced inconsistent effects on physiological stress responses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sensitivity to the locomotor stimulant effects of ethanol and allopregnanolone is influenced by common genes.

Allopregnanolone is a neuroactive steroid that, like ethanol (EtOH), has stimulant, anxiolytic, ataxic, and depressant effects. Two experiments tested the hypothesis that sensitivity to the locomotor stimulant effects of these drugs is influenced by a common set of genes. Sensitivity to the locomotor stimulant effects of allopregnanolone was determined in 24 BXD recombinant inbred (RI) strains. Strain means were positively correlated with extant means for EtOH stimulation in 20 of the same strains. Quantitative trait locus (QTL) analysis provisionally identified many loci, including several known to influence sensitivity to EtOH. Sensitivity to allopregnanolone was also measured in FAST and SLOW mice, which were selectively bred for differential locomotor response to EtOH, to determine whether selection has also altered allopregnanolone sensitivity. FAST mice were more sensitive to the stimulant effects of allopregnanolone compared with SLOW mice. These data suggest that sensitivity to the locomotor stimulant effects of these drugs is influenced by common genes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

神经甾体的合成和代谢及其对神经系统作用

神经甾体是指存在于中枢和外周神经系统,不需依赖于内分泌腺体的甾体激素,包括孕烯醇酮、孕酮、别孕烯醇酮、脱氢表雄酮等,由胆固醇或其前体在相应酶的作用下在神经系统合成。神经甾体可以通过作用于GABAA 受体、NMDA 受体和σ受体发挥作用。它们对记忆、睡眠、惊厥、细胞兴奋性毒性等产生相应的作用,为某些疾病的治疗指明方向。     

Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals

Steroid hormones are essential biomolecules for human physiology as they modulate the endocrine system, nervous function and behaviour. Recent studies have shown that the gut microbiota is directly involved in the production and metabolism of steroid hormones in the periphery. However, the influence of the gut microbiota on levels of steroids acting and present in the brain (i.e., neuroactive steroids) is not fully understood. Therefore, using liquid chromatography–tandem mass spectrometry, we assessed the levels of several neuroactive steroids in various brain areas and the plasma of germ-free (GF) male mice and conventionally colonized controls. The data obtained indicate an increase in allopregnanolone levels associated with a decrease in those of 5α-androstane-3α, 17β-diol (3α-diol) in the plasma of GF mice. Moreover, an increase of dihydroprogesterone and isoallopregnanolone in the hippocampus, cerebellum, and cerebral cortex was also reported. Changes in dihydrotestosterone and 3α-diol levels were also observed in the hippocampus of GF mice. In addition, an increase in dehydroepiandrosterone was associated with a decrease in testosterone levels in the hypothalamus of GF mice. Our findings suggest that the absence of microbes affects the neuroactive steroids in the periphery and the brain, supporting the evidence of a microbiota-mediated modulation of neuroendocrine pathways involved in preserving host brain functioning.     

Neurosteroids and Focal Epileptic Disorders

Neurosteroids are a family of compounds that are synthesized in principal excitatory neurons and glial cells, and derive from the transformation of cholesterol into pregnenolone. The most studied neurosteroids—allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC)—are known to modulate GABA_A receptor-mediated transmission, thus playing a role in controlling neuronal network excitability. Given the role of GABA_A signaling in epileptic disorders, neurosteroids have profound effects on seizure generation and play a role in the development of chronic epileptic conditions (i.e., epileptogenesis). We review here studies showing the effects induced by neurosteroids on epileptiform synchronization in in vitro brain slices, on epileptic activity in in vivo models, i.e., in animals that were made epileptic with chemoconvulsant treatment, and in epileptic patients. These studies reveal that neurosteroids can modulate ictogenesis and the occurrence of pathological network activity such as interictal spikes and high-frequency oscillations (80–500 Hz). Moreover, they can delay the onset of spontaneous seizures in animal models of mesial temporal lobe epilepsy. Overall, this evidence suggests that neurosteroids represent a new target for the treatment of focal epileptic disorders.     

Allopregnanolone Promotes Migration and Invasion of Human Glioblastoma Cells through the Protein Tyrosine Kinase c-Src Activation

Glioblastomas (GBs) are the most aggressive and common primary malignant brain tumors. Steroid hormone progesterone (P4) and its neuroactive metabolites, such as allopregnanolone (3α-THP) are synthesized by neural, glial, and malignant GB cells. P4 promotes cellular proliferation, migration, and invasion of human GB cells at physiological concentrations. It has been reported that 3α-THP promotes GB cell proliferation. Here we investigated the effects of 3α-THP on GB cell migration and invasion, the participation of the enzymes involved in its metabolism (AKR1C1-4), and the role of the c-Src kinase in 3α-THP effects in GBs. 3α-THP 100 nM promoted migration and invasion of U251, U87, and LN229 human-derived GB cell lines. We observed that U251, LN229, and T98G cell lines exhibited a higher protein content of AKR1C1-4 than normal human astrocytes. AKR1C1-4 silencing did not modify 3α-THP effects on migration and invasion. 3α-THP activated c-Src protein at 10 min (U251 cells) and 15 min (U87 and LN229 cells). Interestingly, the pharmacological inhibition of c-Src decreases the promoting effects of 3α-THP on cell migration and invasion. Together, these data indicate that 3α-THP promotes GB migration and invasion through c-Src activation.     

四氢孕酮和地西泮对暴露于架高十字迷宫小鼠的作用

目的 比较孕酮的还原性代谢产物四氢孕酮和地西泮抗焦虑作用。方法 C57小鼠腹腔注射四氢孕酮 、地西泮或赋形剂,20 min 后观察在架高十字迷宫试验中的表现,测定其自发活动 。结果 腹腔注射四氢孕酮 0.1mg·kg^-1,明显缩短小鼠进入十字迷宫开臂的潜伏期[ 从(31.30±8.39)s 减少到 (8.80±6.00)s,P<0.001],并显著增加进入十字迷宫开臂的次数 (从 1.20±0.42 增到4.80±1.75,P<0.001) 及在开臂的滞留时间占总时间的百分比 (从 7.13%增加到 32.50%,P<0.001) 。而腹腔注射地西泮 0.25 mg·kg^-1的抗焦虑作用弱于四氢孕酮 。自发活动实验显示,0.5 mg·kg^-1地西泮明显减少小鼠自发活动 (P<0.01),而 0.1mg·kg^-1地西泮和 0.25 mg·kg^-1的四氢孕酮均不影响小鼠自发活动。结论 试验结果提示神经甾体和地西泮对小鼠行为有不同的作用 。四氢孕酮具选择性抗焦虑作用而不影响自发活动,可望成为地西泮抗焦虑的代用品。     

Allopregnanolone: Metabolism,Mechanisms of Action,and Its Role in Cancer

Allopregnanolone (3α-THP) has been one of the most studied progesterone metabolites for decades. 3α-THP and its synthetic analogs have been evaluated as therapeutic agents for pathologies such as anxiety and depression. Enzymes involved in the metabolism of 3α-THP are expressed in classical and nonclassical steroidogenic tissues. Additionally, due to its chemical structure, 3α-THP presents high affinity and agonist activity for nuclear and membrane receptors of neuroactive steroids and neurotransmitters, such as the Pregnane X Receptor (PXR), membrane progesterone receptors (mPR) and the ionotropic GABA_A receptor, among others. 3α-THP has immunomodulator and antiapoptotic properties. It also induces cell proliferation and migration, all of which are critical processes involved in cancer progression. Recently the study of 3α-THP has indicated that low physiological concentrations of this metabolite induce the progression of several types of cancer, such as breast, ovarian, and glioblastoma, while high concentrations inhibit it. In this review, we explore current knowledge on the metabolism and mechanisms of action of 3α-THP in normal and tumor cells.     

Organ Weights in NPC1 Mutant Mice Partly Normalized by Various Pharmacological Treatment Approaches

Niemann-Pick Type C1 (NPC1, MIM 257220) is a rare, progressive, lethal, inherited autosomal-recessive endolysosomal storage disease caused by mutations in the NPC1 leading to intracellular lipid storage. We analyzed mostly not jet known alterations of the weights of 14 different organs in the BALB/cNctr-Npc1^m1N/-J Jackson Npc1 mice in female and male Npc1^+/+ and Npc1^−/− mice under various treatment strategies. Mice were treated with (i) no therapy, (ii) vehicle injection, (iii) a combination of miglustat, allopregnanolone, and 2-hydroxypropyl-ß-cyclodextrin (HPßCD), (iv) miglustat, and (v) HPßCD alone starting at P7 and repeated weekly throughout life. The 12 respective male and female wild-type mice groups were evaluated in parallel. In total, 351 mice (176 Npc1^+/+, 175 Npc1^−/−) were dissected at P65. In both sexes, the body weights of None and Sham Npc1^−/− mice were lower than those of respective Npc1^+/+ mice. The influence of the Npc1 mutation and/or sex on the weights of various organs, however, differed considerably. In males, Npc1^+/+ and Npc1^−/− mice had comparable absolute weights of lungs, spleen, and adrenal glands. In Npc1^−/− mice, smaller weights of hearts, livers, kidneys, testes, vesicular, and scent glands were found. In female Npc1^−/− mice, ovaries, and uteri were significantly smaller. In Npc1^−/− mice, relative organ weights, i.e., normalized with body weights, were sex-specifically altered to different extents by the different therapies. The combination of miglustat, allopregnanolone, and the sterol chelator HPßCD partly normalized the weights of more organs than miglustat or HPßCD mono-therapies.     

Rats bred for high versus low anxiety responses neonatally demonstrate increases in lordosis, pacing behavior, and midbrain 3α,5α-THP levels as adults.

Duration and intensity of lordosis is mediated by actions of the progesterone (P) metabolite, 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP) at GABAA receptors in the midbrain ventral tegmental area. Because rats selectively bred for infantile vocalizations may differ in endogenous 3α,5α-THP secretion, their sexual behavior, midbrain, and plasma 3α,5α-THP levels as adult rats in behavioral estrus was examined. Rats bred for high rates of infantile vocalizations had shorter latencies and intervals between intromissions and ejaculation, higher lordosis quotients and ratings, more pacing of their sexual contacts, and had higher P and 3α,5α-THP levels in plasma and midbrain than did rats bred for low rats of infantile vocalizations. Thus, levels of 3α,5α-THP in the midbrain are associated with differences in sexual behavior of these rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)