Allosteric modulators of extrasynaptic delta-GABAA receptors for the treatment of postpartum depression

产后抑郁症(PPD)是常见的“婴儿忧郁症”的更严重版本，15%-20%的母亲会发生，并与抑郁情绪、焦虑和无价值感等症状有关。虽然原因尚不清楚，但据推测，产后抑郁是由出生后一种名为别孕酮的化学物质数量减少引发的，众所周知，这种化学物质对大脑功能和情绪有影响。最近，当别孕酮补充策略被证明在缓解抑郁症状方面有效时，这一假设得到了证实，并被美国食品和药物管理局批准用于治疗患有PPD的母亲。然而，这种名为Brexanolone(但只是别孕酮的专利形式)的药物存在许多与其使用相关的重大问题，尤其是需要60小时静脉输液、严重的副作用和非常高的成本。因此，Brexanolone在更广泛的PPD患者群体中的可获得性有限。Brexanolone通过改变大脑中一组称为GABAA受体(GABAARs)的蛋白质的功能来发挥作用。有证据表明，这些蛋白中的一种，即所谓的突触外GABAARs，是Brexanolone治疗PPD的有益效果的原因，而其他亚型的GABAAR蛋白则是副作用的原因。在这项建议中，我们的目标是确定改变突触外GABAAR蛋白功能但不影响那些导致副作用的蛋白的化学物质。作为将这些化合物推向临床和PPD患者群体的下一步，我们还将证明这些化学物质选择性地改变完整的小鼠和大鼠脑组织中突触外GABAAR蛋白的功能。如果这个项目成功，然后我们实现了我们的最终长期目标，即确定一种治疗产后抑郁的药物，那么我们相信它可以为产后抑郁症的治疗提供一个阶段性的改变。因此，本提案是在产妇心理健康领域产生重大影响的进程中重要的第一步。

Postpartum depression (PPD), which is a more severe version of the common "baby blues", occurs in 15-20% of mothers and is associated with symptoms such as depressed mood, anxiety and feelings of worthlessness. Although the cause is unknown, it is hypothesised that PPD is triggered by the reduction after birth in the amount of a chemical called allopregnanolone which is well-known to have an effect on brain function and mood. This hypothesis was recently confirmed when an allopregnanolone-supplement strategy was shown to be effective in alleviating the symptoms of depression and was approved by the US Food and Drug Adminstration for the treatment of mothers with PPD. However, the drug, which is called Brexanolone (but is simply a proprietary form of allopregnanolone), has a number of significant issues associated with its use, not least of which are the need for a 60-hour intravenous infusion, serious side effects and a very high cost. As a result, Brexanolone has limited availability to the wider PPD patient population.Brexanolone works by altering the function of a group of proteins in the brain called the GABAA receptors (GABAARs). Evidence suggests that one type of these proteins, the so-called extrasynaptic GABAARs are responsible for the beneficial effects of Brexanolone in the treatment of PPD whereas other other subtypes of GABAAR proteins are responsible for the side effects. In this proposal we aim to identify chemicals that alter the function of the extrasynaptic GABAAR proteins but do not affect those proteins responsible for the side-effects. As the next step in advancing such compounds towards the clinic and the PPD patient population, we will also demonstrate that these chemicals selectively alter the function of the extrasynaptic GABAAR proteins in intact mouse and rat brain tissue. If this project is successful and we then achieve our ultimate long-term goal of identifying a drug for treating PPD, then we believe that it could provide a step-change in the treatment of postpartum depression. As such, this present proposal represents an important first step in the process of making a significant impact within the field of maternal mental health.