Role of Brain Estradiol in the Treatment of Male Depression and Anxiety

描述(申请人提供)：男性大脑含有大量的17b-雌二醇(E2)，这是由于芳香酶从睾酮转化而来的，以及雌激素受体，一旦激活，就会启动一些与抑郁症治疗有关的信号通路。然而，在抑郁和焦虑的动物模型中，雌二醇对男性行为的影响只得到了有限的考虑。同样，雌二醇的潜在有益作用 对男性的研究仅限于有限的程度，部分原因是它的潜在副作用，包括女性化。因此，对于一些患者来说，脑选择性E2治疗可能是对现有治疗的改善，现有治疗导致对大多数患者的治疗不充分。因此，对用于临床前研究、人类男性概念验证和未来临床治疗研究的新的、更安全的E2疗法的巨大需求尚未得到满足。在此，我们建议在抑郁和焦虑的动物模型上测试10b，17b-二羟基-1，4-二烯-3-酮(DHed)--一种创新的化合物，根据其独特的作用机制被归类为E2的脑选择性生物递归前体药物。基于令人鼓舞的初步数据，我们的目标是确定大脑选择性E2在治疗男性抑郁和焦虑方面的可能好处。我们的中心假设是，大脑选择性E2治疗将在雄性小鼠身上产生抗抑郁和缓解焦虑的效果。这一假设得到了我们的研究的支持，在这些研究中，给雄性和雌性啮齿动物注射DHED会在大脑中产生显着的E2水平。此外，我们的初步数据表明，给予dhed在雌性小鼠身上具有抗抑郁和缓解焦虑的类似作用，并且很可能在 雄鼠。在第一个具体目标中，我们将定义大脑选择性E2治疗的范围 DHED对雄性小鼠抑郁和焦虑样行为的影响。这些研究将包括急性和慢性给药、剂量-反应曲线，以及涉及性腺完整和切除的男性的研究。我们假设，从全身给药的DHED形成的E2将在雄性小鼠中产生强大的抗抑郁和抗焦虑样作用，并且E2将逆转兰花摘除对抑郁和焦虑结果的有害影响。在第二个特定目标中，我们将通过生物分析方法确定与行为和细胞内信号通路活性相关的脑选择性DHed分布和对E2的生物激活。我们将重点研究急性和慢性全身给药后靶(CNS)和非靶(外周)组织以及循环中E2的测量。我们将把特定目标1的所有行为结果与大脑中的E2水平相关联，这将是有史以来第一项在男性中将大脑中的E2浓度与焦虑和抑郁相关的行为结果联系起来的研究。成功完成拟议的实验将使我们能够得出结论，是否将大脑选择性E2疗法作为男性抑郁和焦虑的潜在治疗方法，并为未来支持啮齿动物和人类在其他各种男性中枢神经系统疾病中测试大脑选择性E2提供概念验证。

DESCRIPTION (provided by applicant): The male brain contains significant concentrations of 17b-estradiol (E2), due to conversion from testosterone by aromatase, and estrogen receptors that upon activation initiate a number of signaling pathways implicated in the treatment of depression. However, the effects of E2 on male behavior in animal models of depression and anxiety have received only limited consideration. Similarly, the potential beneficial effects of E2 in male humans have been studied only to a limited degree, in part due to its potential side effects including feminization. As such, brain-selective E2 therapy could, for some patients, be an improvement over existing treatments, which result in inadequate treatment for the majority of patients. Therefore, there is a huge unmet need for a new and safer E2 therapy for preclinical studies, as well as human male proof of concept and future clinical treatment studies. Herein, we propose to test, in animal models of depression and anxiety, 10b,17b- dihydroxyestra-1,4-dien-3-one (DHED)-an innovative compound classified according to its unique mechanism of action as a brain-selective bioprecursor prodrug of E2. Based on encouraging preliminary data, we aim at establishing the possible benefits of brain-selective E2 in the treatment of depression and anxiety in males. Our central hypothesis is that brain selective E2 treatment wil result in antidepressant- and anxiolytic-like effects in male mice. This hypothesis is supported by our studies where administration of DHED to male and female rodents produced significant E2 levels in the brain. Further, our preliminary data indicates that administration of DHED has antidepressant- and anxiolytic-like effects in female mice and is likely to have similar effects in male mice. In the first Specific Aim, we will define the range of brain-selective E2 treatment with DHED on depression- and anxiety-like behaviors in male mice. These studies will encompass acute and chronic administrations, dose-response curves, and studies involving gonadally intact and orchidectomized males. We hypothesize that E2 formed from the systemically administered DHED will result in robust antidepressant- and anxiolytic-like effects in male mice and that E2 will reverse deleterious effects of orchidectomy on depression and anxiety outcomes. In the second Specific Aim, we will identify, through bioanalytical methods, brain-selective DHED distribution and bioactivation to E2 that associate with behaviors and intracellular signaling pathway activity. We will focus on the measurement of E2 in target (CNS) and non- target (peripheral) tissues and in the circulation after acute and chronic systemic administration. We wil correlate all behavioral outcomes in Specific Aim 1 with brain levels of E2, which will be the first study ever in males to link brain concentration of E2 to anxiety- and depression-related behavioral outcomes. Successful completion of the proposed experiments will allow us to conclude whether to move forward with brain-selective E2 therapy as a potential treatment of depression and anxiety in men, and provide proof-of-concept to support future rodent and human testing of brain selective E2 in various other CNS diseases in males.