The impact of diazepam’s discovery on the treatment and understanding of status epilepticus

Summary The fortuitous discovery of the benzodiazepines and the subsequent application of these agents to the treatment of status epilepticus (SE) heralds in the modern age of treating this neurologic emergency. More than 50 years after their discovery, the benzodiazepines remain the drugs of first choice in the treatment of SE. However, the benzodiazepines can be ineffective, especially in those patients whose seizures are the most prolonged. The benzodiazepines act by increasing the affinity of γ‐aminobutyric acid (GABA) for GABA A receptors. A receptor’s subunit composition affects its functional and pharmacologic properties, trafficking, and cellular localization. The GABA A receptors that mediate synaptic inhibition typically contain a γ2 subunit and are diazepam‐sensitive. Among the GABA A receptors that mediate tonic inhibition are the benzodiazepine‐insensitive δ subunit–containing receptors. The initial studies investigating the pathogenesis of SE demonstrated that a reduction in GABA‐mediated inhibition within the hippocampus was important in maintenance of SE, and this reduction correlated with a rapid modification in the postsynaptic GABA A receptor population expressed on the surface of the hippocampal principal neurons. Subsequent studies found that this rapid modification is, in part, mediated by an activity‐dependent, subunit‐specific trafficking of the receptors that resulted in the reduction in the surface expression of the benzodiazepine‐sensitive γ2 subunit–containing receptors and the preserved surface expression of the benzodiazepine‐insensitive δ subunit‐containing receptors. This improved understanding of the changes in the trafficking of GABA A receptors during SE partially accounts for the development of benzodiazepine‐pharmacoresistance and has implications for the current and future treatment of benzodiazepine‐refractory SE.