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The impact of diazepam's discovery on the treatment and understanding of status epilepticus.
Epilepsia. 2009 Sep; 50(9):2011-8.E

Abstract

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 gamma-aminobutyric acid (GABA) for GABAA receptors. A receptor's subunit composition affects its functional and pharmacologic properties, trafficking, and cellular localization. The GABAA receptors that mediate synaptic inhibition typically contain a gamma2 subunit and are diazepam-sensitive. Among the GABAA receptors that mediate tonic inhibition are the benzodiazepine-insensitive delta 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 GABAA 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 gamma2 subunit-containing receptors and the preserved surface expression of the benzodiazepine-insensitive delta subunit-containing receptors. This improved understanding of the changes in the trafficking of GABAA receptors during SE partially accounts for the development of benzodiazepine-pharmacoresistance and has implications for the current and future treatment of benzodiazepine-refractory SE.

Authors+Show Affiliations

Department of Neurology, University of Virginia Health systems, Charlottesville, Virginia 22908, USA. hpg9v@virginia.eduNo affiliation info available

Pub Type(s)

Historical Article
Journal Article

Language

eng

PubMed ID

19674049

Citation

Goodkin, Howard P., and Jaideep Kapur. "The Impact of Diazepam's Discovery On the Treatment and Understanding of Status Epilepticus." Epilepsia, vol. 50, no. 9, 2009, pp. 2011-8.
Goodkin HP, Kapur J. The impact of diazepam's discovery on the treatment and understanding of status epilepticus. Epilepsia. 2009;50(9):2011-8.
Goodkin, H. P., & Kapur, J. (2009). The impact of diazepam's discovery on the treatment and understanding of status epilepticus. Epilepsia, 50(9), 2011-8. https://doi.org/10.1111/j.1528-1167.2009.02257.x
Goodkin HP, Kapur J. The Impact of Diazepam's Discovery On the Treatment and Understanding of Status Epilepticus. Epilepsia. 2009;50(9):2011-8. PubMed PMID: 19674049.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The impact of diazepam's discovery on the treatment and understanding of status epilepticus. AU - Goodkin,Howard P, AU - Kapur,Jaideep, Y1 - 2009/08/08/ PY - 2009/8/14/entrez PY - 2009/8/14/pubmed PY - 2009/9/2/medline SP - 2011 EP - 8 JF - Epilepsia JO - Epilepsia VL - 50 IS - 9 N2 - 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 gamma-aminobutyric acid (GABA) for GABAA receptors. A receptor's subunit composition affects its functional and pharmacologic properties, trafficking, and cellular localization. The GABAA receptors that mediate synaptic inhibition typically contain a gamma2 subunit and are diazepam-sensitive. Among the GABAA receptors that mediate tonic inhibition are the benzodiazepine-insensitive delta 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 GABAA 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 gamma2 subunit-containing receptors and the preserved surface expression of the benzodiazepine-insensitive delta subunit-containing receptors. This improved understanding of the changes in the trafficking of GABAA receptors during SE partially accounts for the development of benzodiazepine-pharmacoresistance and has implications for the current and future treatment of benzodiazepine-refractory SE. SN - 1528-1167 UR - https://www.unboundmedicine.com/medline/citation/19674049/The_impact_of_diazepam's_discovery_on_the_treatment_and_understanding_of_status_epilepticus_ L2 - https://doi.org/10.1111/j.1528-1167.2009.02257.x DB - PRIME DP - Unbound Medicine ER -