Clinical Potential of Neurosteroids for CNS Disorders

Abstract

Summary 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.

Zinc Selectively Blocks Neurosteroid-Sensitive Extrasynaptic GABAA Receptors in the Hippocampus

“…We observed potent Zn 2ϩ blockade of neurosteroid-sensitive tonic currents but not phasic currents. A previous study reported inhibition of phasic currents by Zn 2ϩ (Ruiz et al, 2004); however, we demonstrate that neurosteroid-mediated GABA A receptor potentiation overcomes Zn 2ϩ depression of synaptic receptors. Because of the high affinity for ␦-containing receptors, Zn 2ϩ and neurosteroids influence inhibition through opposing action, albeit at different allosteric sites (Hosie et al, 2003 function may be quite different from its role in pathological states, such as epilepsy.…”

“…Seizure experiments were conducted using hippocampus kindling model (Reddy and Mohan, 2011;Reddy et al, 2015). Mice were anesthetized by intraperitoneal injection of ketamine (100 mg/kg) and xylazine (10 mg/kg).…”

“…By demonstrating that extracellular Zn 2ϩ prevents neurosteroid augmentation of tonic current and protection against limbic seizures, our findings provide novel implications of this potential antagonistic interaction in a variety of neurological conditions. mossy fiber synaptic varicosities that release GABA (Ruiz et al, 2004;Bitanihirwe and Cunningham, 2009). Excessive release of Zn 2ϩ has been reported in epilepsy (Takeda et al, 1999), and it can elicit excitatory and proconvulsant effects (Foresti et al, 2008).…”

“…Neurosteroids, such as allopregnanolone (AP), are positive allosteric modulators of synaptic and extrasynaptic GABA A receptors and exhibit a greater potency for extrasynaptic ␦-containing receptors (Spigelman et al, 2003;Stell et al, 2003;Reddy and Jian, 2010). AP potentiates tonic current in DGGCs and provides robust protection against a variety of seizures and status epilepticus (Carver et al, 2014;Reddy and Estes, 2016).…”

“…AP potentiates tonic current in DGGCs and provides robust protection against a variety of seizures and status epilepticus (Carver et al, 2014;Reddy and Estes, 2016). Zn 2ϩ and neurosteroids have preferential affinity for ␦-containing receptors Reddy, 2013, 2016).…”