New directions in neurosteroid therapeutics in neuropsychiatry
Charles F. Zorumski, Douglas F. Covey, Yukitoshi Izumi, Alex S. Evers, Jamie Maguire, Steven Mennerick
Abstract
In recent years three neuroactive steroids (NAS), brexanolone (allopregnanolone, AlloP), ganaxolone and zuranolone, have been approved for the treatment of neuropsychiatric illnesses including postpartum depression and seizures in a neurodevelopmental syndrome. The approved agents are pregnane steroids and strong positive allosteric modulators (PAMs) of gamma-aminobutyric acid type A receptors (GABA A Rs). Broad effects on GABA A Rs play important roles in therapeutic benefits. However, these NAS also have actions on non-GABAR targets that could be important for clinical outcomes. Thus, understanding the broader effects of NAS is potentially important for expanding the therapeutic landscape of these important modulators. The approved NAS as well as other structurally distinct NAS and oxysterols have effects on non-GABA A R receptors and ion channels, along with intracellular actions that could have therapeutic importance, including modulation of cellular stress mechanisms, neuroinflammation, mitochondrial function and autophagy, among others. In this review, we explore GABAergic and other cellular effects of pregnane steroids including novel molecules that have potential therapeutic importance. This work discusses the complex chemical nature of NAS and what is being learned at cellular, molecular, synaptic and brain network levels about key sites of action including GABA A Rs and other targets. • Three neuroactive steroids (NAS) are now FDA approved for clinical use. • The approved NAS are potent and effective positive modulators of GABA A Rs. • NAS also have important effects on neuroinflammation and cellular stress. • NAS that inhibit GABA A Rs and that modulate NMDARs are potentially novel therapeutics.