Neurosteroids are endogenous modulators of neuronal excitability and plasticity.   They are synthesized in glial cells and in some neurons.  Neurosteroids affect neuronal function by modulating neurotransmitter-gated ion channels and G-protein-coupled receptors.  Neurosteroids act as paracrine chemical signals that diffuse via the extra cellular fluid to affect neighboring target cells.  Neurosteroids have been implicated in neurodegenerartion, neuroprotection and psychiatric disorders, as well as epileptogenesis and hepatic encephalopathy. 

Drugs that affect synthesis or metabolism of neurosteroids provide new therapeutic options. Changes on brain neurosteroid levels occur with aging, stress, menstrual cycle, pregnancy, menopause, neurologic and psychiatric disorders.  These changes affect cognition; sleep patterns, affect and neuronal excitability.  For example, progesterone increases seizure threshold as it converts to allopregnanolone.  And abrupt falls in plasma progesterone prior to menstruation have been implicated in the pathophysiology of catamenial epilepsy.  Medroxyprogesterone, an oral contraceptive agent, has an anticonvulsant effect in catmenial epilepsy.

The synergistic affect between neurosteroids and benzodiazepines on the GABA a receptor complex, have shown promise when flumazenil is used in hepatic encephalopathy (HE).  HE is associated with increased brain expression of the mitochondrial peripheral-type benzodiazepine receptor.  Neurosteroids have been linked to the pathogenesis of HE. 

Production of neurosteroids is increased in traumatic brain injury, cerebral ischemia, MS and other disorders.  Experimental evidence is suggesting that the involvement of neurosteroids in neurodegenerative mechanism indicate that these neurochemical signals play a role in the pathogenesis of neuroprotective therapy for disorders such as AD, Parkinson disease and ALS.  Neurosteroids are one more indication of the multiple neurochemical signals regulating neuronal development, function and plasticity.  Drugs affecting the synthesis or metabolism of neurosteroids may provide new therapeutic tools for use in neurodegernative diseases.  We expect to see much more research on this topic.

gizell.larson@neurosciencegroup.com  susan.hibbs@neurosciencegroup.com
steven.price@neurosciencegroup.com   lisa.kokontis@neurosciencegroup.com
thomas.mattio@neurosciencegroup.com