Antiseizure Activity of Midazolam in Mice Lacking δ-Subunit Extrasynaptic GABA(A) Receptors

The Journal of Pharmacology and Experimental Therapeutics
Sandesh D ReddyD S Reddy

Abstract

Midazolam is a benzodiazepine anticonvulsant with rapid onset and short duration of action. Midazolam is the current drug of choice for acute seizures and status epilepticus, including those caused by organophosphate nerve agents. The antiseizure activity of midazolam is thought to result from its allosteric potentiation of synaptic GABA(A) receptors in the brain. However, there are indications that benzodiazepines promote neurosteroid synthesis via the 18-kDa cholesterol transporter protein (TSPO). Therefore, we investigated the role of neurosteroids and their extrasynaptic GABA(A) receptor targets in the antiseizure activity of midazolam. Here, we used δ-subunit knockout (DKO) mice bearing a targeted deletion of the extrasynaptic receptors to investigate the contribution of the extrasynaptic receptors to the antiseizure activity of midazolam using the 6-Hz and hippocampus kindling seizure models. In both models, midazolam produced rapid and dose-dependent protection against seizures (ED50, 0.4 mg/kg). Moreover, the antiseizure potency of midazolam was undiminished in DKO mice compared with control mice. Pretreatment with PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide], a TSPO blocker, or fin...Continue Reading

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Citations

Feb 10, 2016·The Journal of Pharmacology and Experimental Therapeutics·Chase Matthew Carver, Doodipala Samba Reddy
May 6, 2016·Frontiers in Cellular Neuroscience·Doodipala Samba Reddy
Aug 19, 2015·European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology·María Álvaro-Bartolomé, Jesús A García-Sevilla
Feb 27, 2017·Journal of Neuroscience Research·Bryan L Clossen, Doodipala Samba Reddy
Sep 29, 2017·Expert Review of Clinical Pharmacology·Iyan Younus, Doodipala Samba Reddy
Nov 17, 2017·The Journal of Pharmacology and Experimental Therapeutics·Shu-Hui Chuang, Doodipala Samba Reddy
Jul 28, 2016·Annals of the New York Academy of Sciences·Doodipala Samba Reddy
Sep 14, 2018·Epilepsy Research·Doodipala Samba ReddyRama Maganti

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