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].
参考文献:
[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]。
| 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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参考文献: [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] :Brunton P J, McKay A J, Och?dalski 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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