Clinical Potential of Neurosteroids for CNS Disorders.
Clinical Potential of Neurosteroids for CNS Disorders.
复制标题
DOI：
10.1016/j.tips.2016.04.003
复制
发表时间：
2016-07
影响因子：
13.8
通讯作者：
Estes WA
中科院分区：
文献类型：
--
作者：
Reddy DS;Estes WA
神经类固醇是大脑中影响许多神经功能的关键内源性分子。在这里，我们描述了 NIH 资助的神经类固醇治疗中枢神经系统疾病的临床研究和其他临床研究的最新进展。神经元 GABA-A 受体氯离子通道是神经类固醇的主要分子靶标之一。四氢孕酮样神经甾体是有效的变构激动剂以及突触和突触外 GABA-A 受体的直接激活剂。因此，神经类固醇可以最大限度地增强突触相性和突触外紧张性抑制。由此产生的氯电流电导产生一种分流抑制形式，控制网络兴奋性、癫痫发作和行为。神经类固醇的此类机制为癫痫、癫痫持续状态、脑损伤、脆性 X 综合征和化学神经毒性提供了创新疗法。神经类固醇领域已经进入了一个新时代，许多化合物已进入高级临床试验。与临床使用的天然神经类固醇相比，合成类似物具有多种优势，因为它们具有优异的生物利用度和安全性。
Neurosteroids are key endogenous molecules in the brain that affect many neural functions. Here, we describe recent advances in NIH-sponsored and other clinical studies of neurosteroids for CNS disorders. The neuronal GABA-A receptor chloride channel is one of the prime molecular targets of neurosteroids. Allopregnanolone-like neurosteroids are potent allosteric agonists as well as direct activators of both synaptic and extrasynaptic GABA-A receptors. Hence, neurosteroids can maximally enhance synaptic phasic and extrasynaptic tonic inhibition. The resulting chloride current conductance generates a form of shunting inhibition that controls network excitability, seizures, and behavior. Such mechanisms of neurosteroids are providing innovative therapies for epilepsy, status epilepticus, brain injury, Fragile X syndrome, and chemical neurotoxicity. The neurosteroid field has entered a new era, as many compounds have reached advanced clinical trials. Synthetic analogs have several advantages over natural neurosteroids for clinical use because of their superior bioavailability and safety trends.