Neurosteroids and oxysterols are cholesterol-derived neuromodulators that target major signaling systems in the mammalian brain, including glutamate, the brain’s major fast excitatory neurotransmitter, and GABA, the major fast inhibitory neurotransmitter. Glutamate and GABA drive much of the brain’s information processing, and participate in a variety of processes that include phasic and tonic neurotransmission, the synaptic plasticity thought to underlie learning and memory, and the pathophysiology of major neuropsychiatric illnesses. Neurosteroids and oxysterols can bidirectionally modulate the glutamate and GABA systems making them attractive candidates for possible drug development. As an example, the endogenous neurosteroid, allopregnanolone, is a potent and highly effective enhancer of GABA-A receptors, and derivatives have therapeutic potential in multiple disorders including epilepsy, major depression, anxiety disorders, sleep disorders, substance use disorders and chronic pain. A GABA-enhancing neuroactive steroid is now in human clinical trials for super-refractory status epilepticus, a life-threatening clinical condition for which there are few effective treatments, and refractory postpartum depression. On the other hand, the endogenous oxysterol, 24S-hydroxy-cholesterold (24S-HC), the brain’s major cholesterol metabolite, was recently found to be a potent enhancer of NMDA type glutamate receptors, and synthetic derivatives of this agent have potential as cognitive enhancers and possibly as antipsychotic medications. This presentation will overview the effects of neurosteroids and oxysterols on GABA and NMDA receptors, highlighting the therapeutic potential of these agents and setting the stage for discussions of drug development opportunities.

Neurosteroids and oxysterols: Big targets and potentially big payoffs

251st National Meeting (2016)

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