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Investigating excitatory GABAergic signalling & benzodiazepine resistance in an in vitro model of status epilepticus
Status epilepticus (SE) describes a state of persistent seizures which are unrelenting. First- line treatment for status epilepticus uses a group of drugs, the benzodiazepines, that promote the action of the major inhibitory neurotransmitter within the brain, gamma (γ)-aminobutyric acid (GABA). In a...
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| Format: | Thesis |
| Language: | English |
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Division of Medical Biochemistry and Structural Biology
2018
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| _version_ | 1867613811880493056 |
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| access_status_str | Open Access |
| author | Burman, Richard J |
| author2 | Raimondo, Joseph V |
| author_browse | Burman, Richard J Raimondo, Joseph V |
| author_facet | Raimondo, Joseph V Burman, Richard J |
| author_sort | Burman, Richard J |
| collection | Thesis |
| description | Status epilepticus (SE) describes a state of persistent seizures which are unrelenting. First- line treatment for status epilepticus uses a group of drugs, the benzodiazepines, that promote the action of the major inhibitory neurotransmitter within the brain, gamma (γ)-aminobutyric acid (GABA). In a subset of patients however, benzodiazepines prove to be ineffective in terminating SE. Previous data from in vitro models has demonstrated that during single seizures, instead of being inhibitory, activation of the GABAA receptor can have an excitatory effect on neurons. To date, it is unknown whether this shift in GABAergic function contributes to SE, nor how it may modulate the anticonvulsant properties of benzodiazepines. In this thesis I explore the role of excitatory GABAergic signaling in an in vitro model of SE and how this may affect the anticonvulsant efficacy of the benzodiazepine, diazepam. Firstly, I confirm that benzodiazepine-resistant SE is prevalent in a South African paediatric population. Secondly, consistent with its established mechanism of action, I show that diazepam enhances GABAAR synaptic currents. Thirdly, using the in vitro 0 Mg²⁺ model of status epilepticus I show that whilst early application of diazepam has anticonvulsant properties, this is lost when the drug is applied during prolonged epileptiform activity. Fourthly, to investigate this phenomenon I use optogenetic activation of GABAergic interneurons to show that interneurons can drive epileptiform discharges during SE-like activity in vitro. Finally, I confirm that during seizure-like events there is a transient shift in GABAergic signaling that is caused by activity driven changes in the transmembrane Cl⁻ gradient. This thesis provides insight into how excitatory GABAergic signaling during prolonged seizures may contribute towards benzodiazepine resistance in SE. I believe that these results are relevant for understanding of the pathophysiology of SE and may help inform optimal treatment protocols for this condition. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/27886 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:42:05.356Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2018 |
| publishDateRange | 2018 |
| publishDateSort | 2018 |
| publisher | Division of Medical Biochemistry and Structural Biology |
| publisherStr | Division of Medical Biochemistry and Structural Biology |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/27886 Investigating excitatory GABAergic signalling & benzodiazepine resistance in an in vitro model of status epilepticus Burman, Richard J Raimondo, Joseph V Katz, Arieh A Medical Biochemistry Status epilepticus (SE) describes a state of persistent seizures which are unrelenting. First- line treatment for status epilepticus uses a group of drugs, the benzodiazepines, that promote the action of the major inhibitory neurotransmitter within the brain, gamma (γ)-aminobutyric acid (GABA). In a subset of patients however, benzodiazepines prove to be ineffective in terminating SE. Previous data from in vitro models has demonstrated that during single seizures, instead of being inhibitory, activation of the GABAA receptor can have an excitatory effect on neurons. To date, it is unknown whether this shift in GABAergic function contributes to SE, nor how it may modulate the anticonvulsant properties of benzodiazepines. In this thesis I explore the role of excitatory GABAergic signaling in an in vitro model of SE and how this may affect the anticonvulsant efficacy of the benzodiazepine, diazepam. Firstly, I confirm that benzodiazepine-resistant SE is prevalent in a South African paediatric population. Secondly, consistent with its established mechanism of action, I show that diazepam enhances GABAAR synaptic currents. Thirdly, using the in vitro 0 Mg²⁺ model of status epilepticus I show that whilst early application of diazepam has anticonvulsant properties, this is lost when the drug is applied during prolonged epileptiform activity. Fourthly, to investigate this phenomenon I use optogenetic activation of GABAergic interneurons to show that interneurons can drive epileptiform discharges during SE-like activity in vitro. Finally, I confirm that during seizure-like events there is a transient shift in GABAergic signaling that is caused by activity driven changes in the transmembrane Cl⁻ gradient. This thesis provides insight into how excitatory GABAergic signaling during prolonged seizures may contribute towards benzodiazepine resistance in SE. I believe that these results are relevant for understanding of the pathophysiology of SE and may help inform optimal treatment protocols for this condition. 2018-05-03T12:23:56Z 2018-05-03T12:23:56Z 2018 Master Thesis Masters MSc (Med) http://hdl.handle.net/11427/27886 eng application/pdf Division of Medical Biochemistry and Structural Biology Faculty of Health Sciences University of Cape Town |
| spellingShingle | Medical Biochemistry Burman, Richard J Investigating excitatory GABAergic signalling & benzodiazepine resistance in an in vitro model of status epilepticus |
| thesis_degree_str | Master's |
| title | Investigating excitatory GABAergic signalling & benzodiazepine resistance in an in vitro model of status epilepticus |
| title_full | Investigating excitatory GABAergic signalling & benzodiazepine resistance in an in vitro model of status epilepticus |
| title_fullStr | Investigating excitatory GABAergic signalling & benzodiazepine resistance in an in vitro model of status epilepticus |
| title_full_unstemmed | Investigating excitatory GABAergic signalling & benzodiazepine resistance in an in vitro model of status epilepticus |
| title_short | Investigating excitatory GABAergic signalling & benzodiazepine resistance in an in vitro model of status epilepticus |
| title_sort | investigating excitatory gabaergic signalling benzodiazepine resistance in an in vitro model of status epilepticus |
| topic | Medical Biochemistry |
| url | http://hdl.handle.net/11427/27886 |
| work_keys_str_mv | AT burmanrichardj investigatingexcitatorygabaergicsignallingbenzodiazepineresistanceinaninvitromodelofstatusepilepticus |