Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus
Status epilepticus is defined as a state of unrelenting seizure activity. Generalized convulsive status epilepticus is associated with a rapidly rising mortality rate, and thus constitutes a medical emergency. Benzodiazepines, which act as positive modulators of chloride (Cl−) permeable GABAA recept...
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| Fformat: | Journal article |
| Iaith: | English |
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Oxford University Press
2019
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| _version_ | 1826256588233506816 |
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| author | Burman, RJ Selfe, JS Lee, JH Van Den Berg, M Calin, A Codadu, NK Wright, R Newey, SE Parrish, RR Katz, AA Wilmshurst, JM Akerman, CJ Trevelyan, AJ Raimondo, JV |
| author_facet | Burman, RJ Selfe, JS Lee, JH Van Den Berg, M Calin, A Codadu, NK Wright, R Newey, SE Parrish, RR Katz, AA Wilmshurst, JM Akerman, CJ Trevelyan, AJ Raimondo, JV |
| author_sort | Burman, RJ |
| collection | OXFORD |
| description | Status epilepticus is defined as a state of unrelenting seizure activity. Generalized convulsive status epilepticus is associated with a rapidly rising mortality rate, and thus constitutes a medical emergency. Benzodiazepines, which act as positive modulators of chloride (Cl−) permeable GABAA receptors, are indicated as first-line treatment, but this is ineffective in many cases. We found that 48% of children presenting with status epilepticus were unresponsive to benzodiazepine treatment, and critically, that the duration of status epilepticus at the time of treatment is an important predictor of non-responsiveness. We therefore investigated the cellular mechanisms that underlie acquired benzodiazepine resistance, using rodent organotypic and acute brain slices. Removing Mg2+ ions leads to an evolving pattern of epileptiform activity, and eventually to a persistent state of repetitive discharges that strongly resembles clinical EEG recordings of status epilepticus. We found that diazepam loses its antiseizure efficacy and conversely exacerbates epileptiform activity during this stage of status epilepticus-like activity. Interestingly, a low concentration of the barbiturate phenobarbital had a similar exacerbating effect on status epilepticus-like activity, while a high concentration of phenobarbital was effective at reducing or preventing epileptiform discharges. We then show that the persistent status epilepticus-like activity is associated with a reduction in GABAA receptor conductance and Cl− extrusion capability. We explored the effect on intraneuronal Cl− using both gramicidin, perforated-patch clamp recordings and Cl− imaging. This showed that during status epilepticus-like activity, reduced Cl− extrusion capacity was further exacerbated by activity-dependent Cl− loading, resulting in a persistently high intraneuronal Cl−. Consistent with these results, we found that optogenetic stimulation of GABAergic interneurons in the status epilepticus-like state, actually enhanced epileptiform activity in a GABAAR dependent manner. Together our findings describe a novel potential mechanism underlying benzodiazepine-resistant status epilepticus, with relevance to how this life-threatening condition should be managed in the clinic. |
| first_indexed | 2024-03-06T18:04:36Z |
| format | Journal article |
| id | oxford-uuid:0102fdcf-3062-4844-a7b2-aa1fe4b86f83 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:04:36Z |
| publishDate | 2019 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:0102fdcf-3062-4844-a7b2-aa1fe4b86f832022-03-26T08:32:32ZExcitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticusJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0102fdcf-3062-4844-a7b2-aa1fe4b86f83EnglishSymplectic Elements at OxfordOxford University Press2019Burman, RJSelfe, JSLee, JHVan Den Berg, MCalin, ACodadu, NKWright, RNewey, SEParrish, RRKatz, AAWilmshurst, JMAkerman, CJTrevelyan, AJRaimondo, JVStatus epilepticus is defined as a state of unrelenting seizure activity. Generalized convulsive status epilepticus is associated with a rapidly rising mortality rate, and thus constitutes a medical emergency. Benzodiazepines, which act as positive modulators of chloride (Cl−) permeable GABAA receptors, are indicated as first-line treatment, but this is ineffective in many cases. We found that 48% of children presenting with status epilepticus were unresponsive to benzodiazepine treatment, and critically, that the duration of status epilepticus at the time of treatment is an important predictor of non-responsiveness. We therefore investigated the cellular mechanisms that underlie acquired benzodiazepine resistance, using rodent organotypic and acute brain slices. Removing Mg2+ ions leads to an evolving pattern of epileptiform activity, and eventually to a persistent state of repetitive discharges that strongly resembles clinical EEG recordings of status epilepticus. We found that diazepam loses its antiseizure efficacy and conversely exacerbates epileptiform activity during this stage of status epilepticus-like activity. Interestingly, a low concentration of the barbiturate phenobarbital had a similar exacerbating effect on status epilepticus-like activity, while a high concentration of phenobarbital was effective at reducing or preventing epileptiform discharges. We then show that the persistent status epilepticus-like activity is associated with a reduction in GABAA receptor conductance and Cl− extrusion capability. We explored the effect on intraneuronal Cl− using both gramicidin, perforated-patch clamp recordings and Cl− imaging. This showed that during status epilepticus-like activity, reduced Cl− extrusion capacity was further exacerbated by activity-dependent Cl− loading, resulting in a persistently high intraneuronal Cl−. Consistent with these results, we found that optogenetic stimulation of GABAergic interneurons in the status epilepticus-like state, actually enhanced epileptiform activity in a GABAAR dependent manner. Together our findings describe a novel potential mechanism underlying benzodiazepine-resistant status epilepticus, with relevance to how this life-threatening condition should be managed in the clinic. |
| spellingShingle | Burman, RJ Selfe, JS Lee, JH Van Den Berg, M Calin, A Codadu, NK Wright, R Newey, SE Parrish, RR Katz, AA Wilmshurst, JM Akerman, CJ Trevelyan, AJ Raimondo, JV Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus |
| title | Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus |
| title_full | Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus |
| title_fullStr | Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus |
| title_full_unstemmed | Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus |
| title_short | Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus |
| title_sort | excitatory gabaergic signalling is associated with benzodiazepine resistance in status epilepticus |
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