Alterations of GABA_A-Receptor Function and Allosteric Modulation During Development of Status Epilepticus

Abstract

Feng H-J, Mathews GC, Kao C, Macdonald RL. Alterations of GABA A -receptor function and allosteric modulation during development of status epilepticus. J Neurophysiol 99: 1285-1293, 2008. First published January 23, 2008 doi:10.1152/jn.01180.2007. Partial limbic seizures in rodents induced by pilocarpine progress from stages I-II (mouth and facial movements; head nodding) to stage III (forelimb clonus) and then progress rapidly to stages IV-V (generalized limbic seizures; rearing, and rearing with falling) followed by status epilepticus (SE). Although limbic seizures in rodents are terminated by benzodiazepines, a group of ␥-aminobutyric acid type A (GABA A )-receptor positive modulators, significant pharmacoresistance to benzodiazepines develops within minutes during SE. The alterations of GABA A -receptor function and allosteric modulation during development of SE are poorly understood. We induced seizures in juvenile rats by administration of lithium followed by pilocarpine, and whole cell recordings of miniature inhibitory postsynaptic currents (mIPSCs) were obtained from hippocampal dentate granule cells in brain slices. Compared with a sham-treated group, mIPSC amplitude was reduced and decay was accelerated at onset of the first occurrence of stage III (S3) seizures [S3(0)], resulting in a reduction in the total charge transfer at S3(0). Recovery of mIPSC amplitude and prolongation of mIPSC decay occurred 30 min after onset of S3 seizures [S3(30)]. The mIPSC frequency was not altered for S3(0) and S3(30) neurons compared with sham neurons. The net enhancement of total charge transfer by diazepam was smaller for S3(30) than that for sham and S3(0) neurons; however, the net reduction of total charge transfer by zinc was greater for S3(30) than that for sham and S3(0) neurons. These findings suggest that substantial plastic changes of GABA A -receptor function and allosteric modulation occur rapidly in neurons from juvenile animals during development of SE.

Ketamine for the treatment of refractory status epilepticus

“…When ketamine is selected for RSE treatment following prolonged SE, it maybe typically suitable after 5-6 anticonvulsants have been found to be ineffective. This treatment choice is summarized from previous successful reports [25,26,29], and the rationale for its use is based on prolonged seizure duration, decreased numbers of active GABA receptors, gradual elevation of NMDA receptor activity, and increased numbers of NMDA receptors [14][15][16]54,55].…”

“…In recent years, many researchers have reported that, during prolonged seizures, the number of activated GABA-A receptors on the postsynaptic membrane gradually decreases, whereas the number of inactive GABA-A receptors increases [14,15]. These changes cause a significant reduction in the efficacy of antiepileptic drugs (AEDs) that target the GABAergic system, such as diazepam, clonazepam, valproic acid, midazolam, propofol, and phenobarbital.…”

Abstracts

“…Ten patients (66.7%) had no lasting seizure reduction, although 3 of these patients initially had a short transient seizure reduction. Two patients decided to stop treatment before 3 months, the rest were followed in average 7.2 months (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) Purpose: To determine the most frequent etiology of symptomatic epilepsy in adult patients and response to antiepileptic drug therapy.…”

“…After our evaluation no one received epilepsy diagnosis. One patient had Meniere's disease, 5 Method: In two prospective, multicentre, double-blind studies, patients (ffi16 years) with genetically ascertained ULD, showing moderate to severe myoclonus (action myoclonus score >30/160), were randomized (1:1:1) to receive twice-daily BRV (study 1: 5 or 150 mg/day; study 2: 50 or 150 mg/day), or placebo. Two-week up-titration followed by 12-week maintenance.…”

“…Out of the forty patients, (31) patients (77%) were seizure-free. (4) Patients had (1)(2)(3)(4)(5) seizures in two years after the surgery. The histopathology of 26 patients was hippocampal sclerosis, (7) patients with cortical dysplasia/ heterotopias, (2) DNET, (3) ganglioglioma, (1) oligodendroglioma and 1 had normal histopathology.…”