21 Feb New Neurosteroids May Target Refractory Epilepsy
MedicalResearch.com Interview with:
Dr. Samba Reddy, PhD, RPh, FAAPS
Neuroscience and Experimental Therapeutics
College of Medicine
Texas A&M University Health Science Center
Medical Research: What is the background for this study? What are the main findings?
Dr. Reddy: Neurosteroids are a group of neuroactive compounds present in the brain. They are known to modulate ionotropic post-synaptic GABA-A receptors, which are the primary mediators of fast inhibitory neurotransmission in the brain. Hence, the neurosteroid—GABA-A receptor system is a critical axis for controlling neuronal excitability in certain brain disorders, such as anxiety and epilepsy. There is new evidence that such neurosteroids can strongly activate extrasynaptic GABA-A receptors, which are located outside of the synapses mainly on soma, dendrites and axons. However, the neurosteroid structure requirement for functional activation of extrasynaptic receptors remains largely unexplored. In this study, we identified a consensus neurosteroid pharmacophore model at extrasynaptic GABA-A receptors for activation of tonic current and seizure protection.
Medical Research: What should clinicians and patients take away from your report?
Dr. Reddy: The presence of extrasynaptic receptors poses a challenge to the current dogma of synaptic receptor-mediated transmission. It is essential to determine the functional role for such receptors to not only help us better understand certain brain diseases but also to design targeted therapies. For example, unlike synaptic GABA-A receptors (targets of clinically used benzodiazepines) that rapidly internalize or desensitize during persistent acute seizures, extrasynaptic receptors remain largely unaffected by similar events. Thus, such a mechanism offers a venue for targeted therapy in treating acute refractory seizures. Neurosteroids, which show preferential activity at extrasynaptic receptors, represent a novel treatment strategy for such benzodiazepine-resistant seizures.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Reddy: Presently there are few specific ligands for extrasynaptic receptors. We hope this study will open a new horizon in this field by providing the critical information on the structure-activity relationship (SAR) for neurosteroid modulation of extrasynaptic GABA-A receptor-mediated tonic inhibition in the brain.
Medical Research: Is there anything else you would like to add?
Dr. Reddy: At the seizure circuit level, neurosteroids are poised to be much more effective countermeasures for acute refractory seizures than are benzodiazepines because they may act as “circuit breakers” rather than “dimming switches” like benzodiazepines, which fail to activate tonic currents.
Dr. Reddy (2016). New Neurosteroids May Target Refractory Epilepsy