title: Clinical Potential of Neurosteroids for CNS Disorders.
abstract: 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.
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA. Electronic address: reddy@medicine.tamhsc.edu.
authors.forename: Doodipala Samba
authors.initials: DS
authors.lastname: Reddy
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Estes
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy; D002493:Central Nervous System Diseases / Q000188:drug therapy*; D018118:Chloride Channels / Q000187:drug effects; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D005600:Fragile X Syndrome / Q000188:drug therapy; D006801:Humans; D007223:Infant; D020258:Neurotoxicity Syndromes / Q000188:drug therapy; D018377:Neurotransmitter Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011293:Premenstrual Syndrome / Q000188:drug therapy; D011963:Receptors, GABA-A / Q000187:drug effects; D013036:Spasms, Infantile / Q000188:drug therapy
chemical_list: D018118:Chloride Channels; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A
keywords: GABA-A receptor; brain injury; epilepsy; neurosteroid; status epilepticus; tonic inhibition