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]。