Lemini C, García-Albor E, Cruz-López B, Matamoros-Trejo G, Martínez-Mota L
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Ciudad Universitaria, Delegación Coyoacán, C.P. 04510 México, D.F., Mexico.
Laboratorio de Farmacología Conductual, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calz. México-Xochimilco 101, Col. San Lorenzo Huipulco, Delegación Tlalpan, C.P. 14370 México, D.F., Mexico.
Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jan 4;64:102-8. doi: 10.1016/j.pnpbp.2015.07.013. Epub 2015 Jul 31.
Estrogens of clinical use produce consistent antidepressant- and anxiolytic-like effects in animal models of menopause. Regulation of the hypothalamic-pituitary-adrenal (HPA) or stress axis, has been proposed as a pathway through which estrogens improve affective-like behaviors. Anticoagulant 17β-aminoestrogens (17β-AEs) butolame and pentolame mimic some effects of estradiol (E2), i.e., on female rodent sexual behavior, with opposite actions on coagulation. However, their psychoactive actions have not been explored. On the basis of similitude with E2's effects, we hypothesized that these 17β-AEs would induce anxiolytic- and antidepressant-like effects, which would be reflected in a reduction of activity in the HPA axis. In ovariectomized female rats, chronic treatment with prolame (60 μg/kg), butolame (65 μg/kg) and pentolame (70 μg/kg) reduced anxiety-like behavior in the elevated plus maze (evidenced by an increase in time in open arms, E2 (40 μg/kg) +176%; prolame +201%; butolame, +237%; and pentolame +295%, in comparison to the control vehicle group 100%). Pentolame also decreased significantly anxiety-like behavior in the burying behavior test. Prolame and E2 produced a significantly antidepressant-like action, which was not induced by butolame and pentolame. Behavioral effects of 17β-AEs (and E2) on anxiety and depression did not follow the same pattern than corticosterone or E2 levels; they also were associated to changes in locomotor activity, evaluated by the open field test. These results constitute the first evidence of specific and selective actions of butolame and pentolame as anxiolytics for females with a hypoestrogenic condition. Results also confirm the potential of prolame as an antidepressant steroid with equivalent actions to E2. Psychoactive properties of 17β-AEs in combinations with reduced adverse effects on coagulation, suggest that 17β-AEs may be a good alternative replacement therapy for women with symptoms associated with menopause.
临床使用的雌激素在更年期动物模型中可产生一致的抗抑郁和抗焦虑样作用。下丘脑-垂体-肾上腺（HPA）轴或应激轴的调节被认为是雌激素改善情感样行为的一条途径。抗凝17β-氨基雌激素（17β-AEs）布托拉米和喷托拉米可模拟雌二醇（E2）的一些作用，如对雌性啮齿动物性行为的影响，而对凝血有相反作用。然而，它们的精神活性作用尚未得到研究。基于与E2作用的相似性，我们假设这些17β-AEs会诱导抗焦虑和抗抑郁样作用，这将反映在HPA轴活性的降低上。在去卵巢雌性大鼠中，用喷托拉米（60μg/kg）、布托拉米（65μg/kg）和喷托拉米（70μg/kg）进行慢性治疗可降低高架十字迷宫中的焦虑样行为（以在开放臂中的停留时间增加为证据，与对照溶剂组100%相比，E2（40μg/kg）增加176%；喷托拉米增加201%；布托拉米增加237%；喷托拉米增加295%）。喷托拉米在埋埋行为试验中也显著降低了焦虑样行为。布托拉米和E2产生了显著的抗抑郁样作用，而布托拉米和喷托拉米未诱导这种作用。17β-AEs（和E2）对焦虑和抑郁的行为作用与皮质酮或E2水平的模式不同；它们还与通过旷场试验评估的运动活动变化有关。这些结果构成了布托拉米和喷托拉米作为低雌激素状态女性抗焦虑药具有特异性和选择性作用的首个证据。结果还证实了喷托拉米作为一种具有与E2等效作用的抗抑郁甾体的潜力。17β-AEs的精神活性特性以及对凝血的不良反应减少，表明17β-AEs可能是有更年期相关症状女性的一种良好替代替代疗法。
