title: Valnoctamide enhances phasic inhibition: a potential target mechanism for the treatment of benzodiazepine-refractory status epilepticus.
abstract: Valnoctamide (VCD), a derivative of valproate, suppresses electrographic seizures in animal models of status epilepticus (SE), even when the seizures are resistant to benzodiazepines (BZDs). We therefore tested the effect of VCD on miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal cells to determine if VCD acts directly on γ-aminobutyric acid (GABA)A receptors. Bath-applied VCD induced a specific, rapid, dose-dependent, and reversible slowing of the decay of mIPSCs (i.e., increased time constant) with no effect on their frequency or amplitude. This is similar to the effect of BZDs on mIPSCs, but the effect of VCD persisted in the presence of the BZD-binding site antagonist flumazenil, and was additive to the effect of the BZD, diazepam. These data suggest that VCD acts through a different binding site than that of BZDs, which likely accounts for its effect on BZD-refractory SE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
authors.affiliation: Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah, U.S.A.
authors.forename: Jay
authors.initials: J
authors.lastname: Spampanato
authors.forename: F Edward
authors.initials: FE
authors.lastname: Dudek
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D001569:Benzodiazepines / Q000493:pharmacokinetics; D056547:CA1 Region, Hippocampal / Q000187:drug effects*; D005442:Flumazenil / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000577:Amides; D000927:Anticonvulsants; D026941:Sodium Channel Blockers; D001569:Benzodiazepines; C045179:valnoctamide; D005442:Flumazenil; D013779:Tetrodotoxin
keywords: Decay rate; GABA receptor; Miniature inhibitory post-synaptic current; Status epilepticus; Valnoctamide