Neuroactive steroids for the treatment of status epilepticus

Abstract

SUMMARY Benzodiazepines are the current first-line standard-of-care treatment for status epilepticus but fail to terminate seizures in about one-third of cases. Synaptic GABAA receptors, which mediate phasic inhibition in central circuits, are the molecular target of benzodiazepines. As status epilepticus progresses, these receptors are internalized and become functionally inactivated, conferring bezodiazepine resistance, which is believed to be a major cause of treatment failure. GABAA receptor positive allosteric modulator neuroactive steroids, such as allopregnanolone, also potentiate synaptic GABAA receptors, but in addition they enhance extrasynaptic GABAA receptors that mediate tonic inhibition. Extrasynaptic GABAA receptors are not internalized and desensitization of these receptors does not occur during continuous seizures in status epilepticus models. Here we review the broad-spectrum antiseizure activity of allopregnanolone in animal seizure models and the evidence for its activity in models of status epilepticus. We also demonstrate that allopregnanolone inhibits ongoing behavioral and electrographic seizures in a model of status epilepticus, even when there is benzodiazepine resistance. Parenteral allopregnanolone may provide an improved treatment for refractory status epilepticus.

First‐in‐man allopregnanolone use in super‐refractory status epilepticus

“…Tolerance and physical dependence after prolonged exposure to barbiturates and benzodiazepines results in a need for increased doses of these toxic drugs and there is a high propensity for seizures recurrence 15. Allopregnanolone has limited systemic side effects,16 and is highly effective in terminating ongoing status epilepticus in animal models 9, 17. These cases provided critical translational evidence of the activity of allopregnanolone in patients with SRSE, that led directly to the treatment of additional patients, including two children 12.…”

“…Allopregnanolone, an endogenous metabolite of progesterone, is a positive allosteric modulator of synaptic and extrasynaptic GABA A receptors making it an attractive agent for use in the treatment of SRSE 10. Studies in animal models support the potential of allopregnanolone in the treatment of refractory status epilepticus 9. Here, we describe the first‐in‐man experience with allopregnanolone in the treatment of SRSE, providing key translational proof of principle to support its clinical development as a novel therapeutic agent.…”

“…Both continuous seizure activity and GABAergic drugs cause synaptic GABA A receptor internalization and desensitization leading to cortical hyperexcitability 6, 7, 8. Extrasynaptic GABA A receptors are not internalized and could be targeted during treatment of SRSE 9. Development of treatments for status epilepticus has largely relied on application of conventional anticonvulsant and anesthetic agents without regard to mechanistic considerations.…”

3β-Methyl-Neurosteroid Analogs Are Preferential Positive Allosteric Modulators and Direct Activators of Extrasynapticδ-Subunitγ-Aminobutyric Acid Type A Receptors in the Hippocampus Dentate Gyrus Subfield

“…Pilocarpine 7 (4-11) ~6 (Briyal and Reddy, 2008;Kokate et al, 1996) Kainic acid ~20 ND (Rogawski et al, 2013) ND, not determined.…”

Brexanolone as adjunctive therapy in super‐refractory status epilepticus

“…Benzodiazepines are the current first‐line therapy for early and established SE. Similar to allopregnanolone, benzodiazepines, such as midazolam, act as PAMs of the GABA A R. Prolonged seizure activity during SE leads to an activity‐dependent internalization and reduction in synaptic, benzodiazepine‐sensitive GABA A receptors,36, 37 which may contribute to benzodiazepines' inability to halt SE in SRSE patients 38, 39…”