Clinical Potential of Neurosteroids for CNS Disorders

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• 作者：Doodipala Samba Reddy¹ ; ^{reddy@medicine.tamhsc.edu" class="auth_mail" title="E-mail the corresponding author} ; William A. Estes¹
• 关键词：brain injury ; epilepsy ; GABA-A receptor ; neurosteroid ; status epilepticus ; tonic inhibition
• 刊名：Trends in Pharmacological Sciences
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：37
• 期：7
• 页码：543-561
• 全文大小：3233 K

文摘

Neurosteroids are key endogenous molecules in the brain that affect many neural functions. We describe here recent advances in US National Institutes of Health (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 (SE), traumatic brain injury (TBI), fragile X syndrome (FXS), and chemical neurotoxicity. The neurosteroid field has entered a new era, and 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.