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Review
, 37 (7), 543-561

Clinical Potential of Neurosteroids for CNS Disorders

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Review

Clinical Potential of Neurosteroids for CNS Disorders

Doodipala Samba Reddy et al. Trends Pharmacol Sci.

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.

Keywords: GABA-A receptor; brain injury; epilepsy; neurosteroid; status epilepticus; tonic inhibition.

Conflict of interest statement

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1. Chemical structures of natural and synthetic neurosteroids
The key stereo specific features of C3-OH and C5-H groups are highlighted for both naturally occurring neurosteroids and their synthetic analogs.
Figure 2
Figure 2. Neurosteroid mechanism of action at synaptic and extrasynaptic GABA-A receptors
Allopregnanolone and related neurosteroids enhance the function of GABA-A receptors, which are pentameric chloride channels. The “neurosteroid binding” sites are distinct from sites for GABA, benzodiazepines and barbiturates. There are two subtypes of GABA-A receptors with different desensitization kinetics. Synaptic GABA-A receptors, which are composed of 2α2βγ subunits, mediate the phasic portion of inhibition in response to action potential-dependent vesicular release of high levels of GABA, while extrasynaptic GABA-A receptors, which are composed of 2α2βδ subunits, primarily contribute to tonic inhibition when exposed to low, ambient levels of GABA. Neurosteroids activate both synaptic and extrasynaptic receptors and enhance the phasic and tonic inhibition, and thereby promote maximal inhibition in the brain. GABA transporters (GAT) in neurons and glia remove synaptically released GABA. Traces illustrate phasic, as IPSCs (left, 3 μM GABA ± 300 nM AP), and tonic currents (right, 1 μM GABA ± 3 μM AP) in dentate gyrus granule cells during neurosteroid allopregnanolone (AP) perfusion in the hippocampus slice recording. The competitive GABA-A receptor antagonist gabazine (SR-95531, 50 μM) was used to confirm the specificity of GABAergic currents.

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