Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma
Glioblastoma (GBM) is the most common and advanced form of primary malignant tumor occurring in the adult central nervous system, and it is frequently associated with epilepsy, a debilitating comorbidity. Seizures are observed both pre- and post-surgical resection, indicating that several pathophysi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.903115/full |
| _version_ | 1818157049751535616 |
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| author | Kate E. Hills Kostas Kostarelos Kostas Kostarelos Robert C. Wykes Robert C. Wykes |
| author_facet | Kate E. Hills Kostas Kostarelos Kostas Kostarelos Robert C. Wykes Robert C. Wykes |
| author_sort | Kate E. Hills |
| collection | DOAJ |
| description | Glioblastoma (GBM) is the most common and advanced form of primary malignant tumor occurring in the adult central nervous system, and it is frequently associated with epilepsy, a debilitating comorbidity. Seizures are observed both pre- and post-surgical resection, indicating that several pathophysiological mechanisms are shared but also prompting questions about how the process of epileptogenesis evolves throughout GBM progression. Molecular mutations commonly seen in primary GBM, i.e., in PTEN and p53, and their associated downstream effects are known to influence seizure likelihood. Similarly, various intratumoral mechanisms, such as GBM-induced blood-brain barrier breakdown and glioma-immune cell interactions within the tumor microenvironment are also cited as contributing to network hyperexcitability. Substantial alterations to peri-tumoral glutamate and chloride transporter expressions, as well as widespread dysregulation of GABAergic signaling are known to confer increased epileptogenicity and excitotoxicity. The abnormal characteristics of GBM alter neuronal network function to result in metabolically vulnerable and hyperexcitable peri-tumoral tissue, properties the tumor then exploits to favor its own growth even post-resection. It is evident that there is a complex, dynamic interplay between GBM and epilepsy that promotes the progression of both pathologies. This interaction is only more complicated by the concomitant presence of spreading depolarization (SD). The spontaneous, high-frequency nature of GBM-associated epileptiform activity and SD-associated direct current (DC) shifts require technologies capable of recording brain signals over a wide bandwidth, presenting major challenges for comprehensive electrophysiological investigations. This review will initially provide a detailed examination of the underlying mechanisms that promote network hyperexcitability in GBM. We will then discuss how an investigation of these pathologies from a network level, and utilization of novel electrophysiological tools, will yield a more-effective, clinically-relevant understanding of GBM-related epileptogenesis. Further to this, we will evaluate the clinical relevance of current preclinical research and consider how future therapeutic advancements may impact the bidirectional relationship between GBM, SDs, and seizures. |
| first_indexed | 2024-12-11T15:08:01Z |
| format | Article |
| id | doaj.art-85cef373e508484f901d5d2899a1110f |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-11T15:08:01Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-85cef373e508484f901d5d2899a1110f2022-12-22T01:00:50ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-06-011510.3389/fnmol.2022.903115903115Converging Mechanisms of Epileptogenesis and Their Insight in GlioblastomaKate E. Hills0Kostas Kostarelos1Kostas Kostarelos2Robert C. Wykes3Robert C. Wykes4Nanomedicine Lab, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United KingdomNanomedicine Lab, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United KingdomCatalan Institute for Nanoscience and Nanotechnology (ICN2), Edifici ICN2, Campus UAB, Barcelona, SpainNanomedicine Lab, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United KingdomDepartment of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United KingdomGlioblastoma (GBM) is the most common and advanced form of primary malignant tumor occurring in the adult central nervous system, and it is frequently associated with epilepsy, a debilitating comorbidity. Seizures are observed both pre- and post-surgical resection, indicating that several pathophysiological mechanisms are shared but also prompting questions about how the process of epileptogenesis evolves throughout GBM progression. Molecular mutations commonly seen in primary GBM, i.e., in PTEN and p53, and their associated downstream effects are known to influence seizure likelihood. Similarly, various intratumoral mechanisms, such as GBM-induced blood-brain barrier breakdown and glioma-immune cell interactions within the tumor microenvironment are also cited as contributing to network hyperexcitability. Substantial alterations to peri-tumoral glutamate and chloride transporter expressions, as well as widespread dysregulation of GABAergic signaling are known to confer increased epileptogenicity and excitotoxicity. The abnormal characteristics of GBM alter neuronal network function to result in metabolically vulnerable and hyperexcitable peri-tumoral tissue, properties the tumor then exploits to favor its own growth even post-resection. It is evident that there is a complex, dynamic interplay between GBM and epilepsy that promotes the progression of both pathologies. This interaction is only more complicated by the concomitant presence of spreading depolarization (SD). The spontaneous, high-frequency nature of GBM-associated epileptiform activity and SD-associated direct current (DC) shifts require technologies capable of recording brain signals over a wide bandwidth, presenting major challenges for comprehensive electrophysiological investigations. This review will initially provide a detailed examination of the underlying mechanisms that promote network hyperexcitability in GBM. We will then discuss how an investigation of these pathologies from a network level, and utilization of novel electrophysiological tools, will yield a more-effective, clinically-relevant understanding of GBM-related epileptogenesis. Further to this, we will evaluate the clinical relevance of current preclinical research and consider how future therapeutic advancements may impact the bidirectional relationship between GBM, SDs, and seizures.https://www.frontiersin.org/articles/10.3389/fnmol.2022.903115/fullgliomaperitumoral borderepilepsyseizuresspreading depolarizations |
| spellingShingle | Kate E. Hills Kostas Kostarelos Kostas Kostarelos Robert C. Wykes Robert C. Wykes Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma Frontiers in Molecular Neuroscience glioma peritumoral border epilepsy seizures spreading depolarizations |
| title | Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma |
| title_full | Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma |
| title_fullStr | Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma |
| title_full_unstemmed | Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma |
| title_short | Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma |
| title_sort | converging mechanisms of epileptogenesis and their insight in glioblastoma |
| topic | glioma peritumoral border epilepsy seizures spreading depolarizations |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.903115/full |
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