Allopregnanolone
(Synonyms: 四氢孕酮) 目录号 : GC14192
A positive modulator of GABAA receptors
Cas No.:516-54-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Stably transfected differentiated Neuro-2A cells |
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Preparation Method |
Stably transfected differentiated Neuro-2A cells, at final confluence of about 80%, were treated with vehicle, Allopregnanolone, THDOC, PGL, PGL-S, DHEA, DHEA-S at concentrations from 0.01 to 30 µM for 5 days. Next, the influence of all the above-listed neurosteroids at the same concentrations (0.01-30 µM) present in the medium for 5 days, on forskolin-stimulated CAT activity was measured in Neuro-2A cells. Forskolin (25µM) was added to the culture medium 24 h before harvesting of the cells. |
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Reaction Conditions |
0.01 to 30 µM for 5 days |
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Applications |
Allopregnanolone and THDOC treatment inhibited in a concentration-dependent manner (1-30 µM) against the CRR-CAT activity. Lower concentrations of Allopregnanolone and THDOC (0.01-0.3 µM) were inactive. |
| Animal experiment [2]: | |
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Animal models |
Female Sprague Dawley rats |
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Preparation Method |
To test whether suppressed HPA axis responses to IL-1β could be mimicked in virgin rats with allopregnanolone treatment, blood samples and brains were collected from virgin rats treated with allopregnanolone (3 and 1 mg/kg, s.c., 20 and 2 h before IL-1β, respectively) or vehicle (15% ethanol in corn oil; 0.5 ml/kg). To verify that the effects of finasteride on HPA responses to IL-1β seen in pregnant rats were attributable to the actions of allopregnanolone, blood samples and brains were also collected from pregnant (day 20-21) rats treated with finasteride and either allopregnanolone or vehicle. |
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Dosage form |
3 and 1 mg/kg, s.c. |
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Applications |
There was a significant effect of allopregnanolone treatment on ACTH secretion in the virgin rats. There was no difference in basal plasma ACTH concentration between vehicle and allopregnanolone-pretreated virgin rats . IL-1β significantly increased ACTH secretion within 15 min in both the vehicle-treated virgins (4.0-fold increase) and the allopregnanolone treated virgins (2.0-fold increase); the response was markedly reduced in the allopregnanolone-treated group (57% of the peak response in the vehicle group). |
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References: [1] :Budziszewska B, Zając A, Basta-Kaim A, et al. Effects of neurosteroids on the human corticotropin-releasing hormone gene[J]. Pharmacological Reports, 2010, 62(6): 1030-1040. [2] :Brunton P J, McKay A J, Ochędalski T, et al. Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone[J]. Journal of Neuroscience, 2009, 29(20): 6449-6460. |
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Allopregnanolone, a 3alpha, 5alpha progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A (GABAA) receptor, exerts antidepressant and neuroprotective action [1]. The levels of this neuroactive steroid as well as its effects are sexdimorphic [2].
Allopregnanolone (3 μM) present in the culture medium for 5 days did not change the amount of active, phosphorylated form of protein kinase B (PKB, Akt) and extracellular signal-regulated kinase (ERK). Allopregnanolone and THDOC inhibited basal and forskolin-induced CRH gene promoter activity in the differentiated Neuro-2A cells [1].
Allopregnanolone treatment exerted protective effects also in experimental models of neurodegeneration. For instance, Allopregnanolone(2 mg/kg, i.p.) is protective against kainic acidinduced excitotoxicity in the hippocampus in vivo [3]. In the nucleus accumbens of learned helplessness rats (i.e., an experimental model of depression) the astroglial glutamate transporter-1 and glutamine synthetase system is normalized by Allopregnanolone treatment [4]. In mood and anxiety disorders, Allopregnanolone (3 mg/kg and 1 mg/kg, s.c) treatment shows sex specific features. This neuroactive steroid attenuates in females, but not in males, the HPA axis responses to interleukin-1β in adult prenatally stressed rats [5].
References:
[1]. Budziszewska B, Zaj?c A, Basta-Kaim A, et al. Effects of neurosteroids on the human corticotropin-releasing hormone gene[J]. Pharmacological Reports, 2010, 62(6): 1030-1040.
[2]. Diviccaro S, Cioffi L, Falvo E, et al. Allopregnanolone: An overview on its synthesis and effects[J]. Journal of Neuroendocrinology, 2022
[3]. Ciriza I, Carrero P, Frye C A, et al. Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus. The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective[J]. Journal of neurobiology, 2006, 66(9): 916-928.
[4]. Nangaku M, Yoshino K, Oda Y, et al. Astroglial glutamate transporter 1 and glutamine synthetase of the nucleus accumbens are involved in the antidepressant-like effects of allopregnanolone in learned helplessness rats[J]. Behavioural Brain Research, 2021, 401: 113092.
[5]. Brunton P J, Donadio M V, Yao S T, et al. 5α-Reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats[J]. Journal of Neuroscience, 2015, 35(2): 666-677.
Allopregnanolone 是一种 3alpha、5alpha 孕酮代谢物，可作为 γ-氨基丁酸 A 型 (GABAA) 受体的有效变构调节剂，发挥抗抑郁和神经保护作用 [1]。这种神经活性类固醇的水平及其作用是两性异形的[2]。
在培养基中存在 5 天的四氢孕酮 (3 μM) 并未改变活性磷酸化形式的蛋白激酶 B（PKB、Akt）和细胞外信号调节激酶 (ERK) 的数量。 Allopregnanolone 和 THDOC 抑制分化的 Neuro-2A 细胞中基础和毛喉素诱导的 CRH 基因启动子活性[1]。
Allopregnanolone 治疗也在神经变性实验模型中发挥保护作用。例如，Allopregnanolone（2 mg/kg，i.p.）在体内可防止红藻氨酸诱导的海马体兴奋性毒性[3]。在习得性无助大鼠（即抑郁症实验模型）的伏隔核中，星形胶质细胞谷氨酸转运体 1 和谷氨酰胺合成酶系统通过四氢孕酮治疗[4] 正常化。在情绪和焦虑障碍中，Allopregnanolone（3 mg/kg 和 1 mg/kg，皮下注射）治疗显示出性别特异性特征。这种具有神经活性的类固醇会减弱成年产前应激大鼠中 HPA 轴对白细胞介素 1β 的反应，但在雌性中不会减弱 [5]。
| Cas No. | 516-54-1 | SDF | |
| 别名 | 四氢孕酮 | ||
| 化学名 | 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone | ||
| Canonical SMILES | O[C@H]1C[C@H]2[C@@](CC1)(C)[C@@H]3[C@@H](CC2)[C@H]4[C@]([C@@H](C(C)=O)CC4)(C)CC3 | ||
| 分子式 | C21H34O2 | 分子量 | 318.49 |
| 溶解度 | Acetonitrile: 1 mg/ml,Ethanol: 1 mg/ml,Methanol: 1 mg/ml | 储存条件 | Store at RT |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.1398 mL | 15.6991 mL | 31.3982 mL |
| 5 mM | 0.628 mL | 3.1398 mL | 6.2796 mL |
| 10 mM | 0.314 mL | 1.5699 mL | 3.1398 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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Allopregnanolone: An overview on its synthesis and effects
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.
The role of allopregnanolone in depression and anxiety
Neuroactive steroids such as allopregnanolone do not only act as transcriptional factors in the regulation of gene expression after intracellular back-oxidation into the 5-α pregnane steroids but may also alter neuronal excitability through interactions with specific neurotransmitter receptors. In particular, certain 3α-reduced metabolites of progesterone such as 3α,5α-tetrahydroprogesterone (allopregnanolone) and 3α,5β-tetrahydroprogesterone (pregnanolone) are potent positive allosteric modulators of the GABA(A) receptor complex. During the last years, the downregulation of neurosteroid biosynthesis has been intensively discussed to be a possible contributor to the development of anxiety and depressive disorder. Reduced levels of allopregnanolone in the peripheral blood or cerebrospinal fluid were found to be associated with major depression, anxiety disorders, premenstrual dysphoric disorder, negative symptoms in schizophrenia, or impulsive aggression. The importance of allopregnanolone for the regulation of emotion and its therapeutical use in depression and anxiety may not only involve GABAergic mechanisms, but probably also includes enhancement of neurogenesis, myelination, neuroprotection, and regulatory effects on HPA axis function. Certain pharmacokinetic obstacles limit the therapeutic use of natural neurosteroids (low bioavailability, oxidation to the ketone). Until now synthetic neuroactive steroids could not be established in the treatment of anxiety disorders or depression. However, the translocator protein (18 kDa) (TSPO) which is important for neurosteroidogenesis has been identified as a potential novel target. TSPO ligands such as XBD 173 increase neurosteroidogenesis and have anxiolytic effects with a favorable side effect profile.
Allopregnanolone in mood disorders: Mechanism and therapeutic development
The neuroactive steroid allopregnanolone (ALLO) is an endogenous positive allosteric modulator of GABA type A receptor (GABAAR), and the down-regulation of its biosynthesis have been attributed to the development of mood disorders, such as depression, anxiety and post-traumatic stress disorder (PTSD). ALLO mediated depression/anxiety involves GABAergic mechanisms and appears to be related to brain-derived neurotrophic factor (BDNF), dopamine receptor, glutamate neurotransmission, and Ca2+ channel. In the clinical, brexanolone, as a newly developed intravenous ALLO preparation, has been approved for the treatment of postpartum depression (PPD). In addition, traditional antidepressants such as selective serotonin reuptake inhibitor (SSRI) could reverse ALLO decline. Recently, the translocation protein (TSPO, 18 kDa), which involves in the speed-limiting step of ALLO synthesis, and ALLO derivatization have been identified as new directions for antidepressant therapy. This review provides an overview of ALLO researches in animal model and patients, discusses its role in the development and treatment of depression/anxiety, and directs its therapeutic potential in future.
Allopregnanolone Mediates Affective Switching Through Modulation of Oscillatory States in the Basolateral Amygdala
Background: Brexanolone (allopregnanolone) was recently approved by the Food and Drug Administration for the treatment of postpartum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators of GABAA (gamma-aminobutyric acid A) receptors, we still do not fully understand how allopregnanolone exerts persistent antidepressant effects.
Methods: We used electroencephalogram recordings in rats and humans along with local field potential, functional magnetic resonance imaging, and behavioral tests in mice to assess the impact of neurosteroids on network states in brain regions implicated in mood and used optogenetic manipulations to directly examine their relationship to behavioral states.
Results: We demonstrated that allopregnanolone and synthetic neuroactive steroid analogs with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound] and zuranolone [SAGE-217, investigational compound]) modulate oscillations across species. We further demonstrated a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for δ-containing GABAA receptors in mediating the ability of neurosteroids to modulate network and behavioral states. Allopregnanolone in the BLA enhances BLA high theta oscillations (6-12 Hz) through δ-containing GABAA receptors, a mechanism distinct from other GABAA positive allosteric modulators, such as benzodiazepines, and alters behavioral states. Treatment with the allopregnanolone analog SGE-516 protects mice from chronic stress-induced disruption of network and behavioral states, which is correlated with the modulation of theta oscillations in the BLA. Optogenetic manipulation of the network state influences the behavioral state after chronic unpredictable stress.
Conclusions: Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.
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 GABAA 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.