Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience.
Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience.
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DOI：
10.12688/f1000research.18758.1
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发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Mohler, Hanns
中科院分区：
文献类型：
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作者：
Luscher, Bernhard;Mohler, Hanns
抑郁症的 GABA 能缺陷假说指出，特定神经回路中 GABA 能传递的缺陷是抑郁症的原因。相反，GABA 传输的增强，包括由选择性血清素再摄取抑制剂或氯胺酮引发的增强，具有抗抑郁作用。 Brexanolone 是一种内源性神经类固醇四氢孕酮的静脉制剂，在治疗产后抑郁症方面表现出临床显着的抗抑郁活性。通过变构增强 GABA A 受体功能，四氢孕酮的抗抑郁活性归因于 GABA 能抑制的增加。此外，四氢孕酮可以通过降低应激反应性齿状颗粒细胞的活性来稳定正常情绪，从而维持弹性行为。因此，四氢孕酮可以通过增强恢复力来增强和延长其抗抑郁活性。 GABA A 受体的神经类固醇结合域的最新结构解析将加速更具选择性的配体的开发，作为潜在的新型中枢神经系统药物。
The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression. By allosterically enhancing GABA A receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition. In addition, allopregnanolone may stabilize normal mood by decreasing the activity of stress-responsive dentate granule cells and thereby sustain resilience behavior. Therefore, allopregnanolone may augment and extend its antidepressant activity by fostering resilience. The recent structural resolution of the neurosteroid binding domain of GABA A receptors will expedite the development of more selective ligands as a potential new class of central nervous system drugs.