Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma.
Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma.
复制标题
DOI：
10.3389/fnmol.2022.903115
复制
发表时间：
2022
影响因子：
4.8
通讯作者：
Wykes, Robert C.
中科院分区：
文献类型：
--
作者：
Hills, Kate E.;Kostarelos, Kostas;Wykes, Robert C.
胶质母细胞瘤（GBM）是发生在成人中枢神经系统的最常见和晚期的原发性恶性肿瘤，它经常与癫痫有关，这是一种使人衰弱的合并症。在手术切除前和手术后都观察到癫痫发作，这表明几种病理生理机制是共同的，但也引发了关于癫痫发生过程在GBM进展过程中如何演变的问题。在原发性GBM中常见的分子突变，即PTEN和p53，以及它们相关的下游效应，已知会影响癫痫发作的可能性。同样，各种肿瘤内机制，如gbm诱导的血脑屏障破坏和肿瘤微环境中胶质瘤-免疫细胞的相互作用也被认为是导致网络高兴奋性的原因。肿瘤周围谷氨酸和氯化物转运蛋白表达的实质性改变，以及gaba能信号的广泛失调，已知会增加致痫性和兴奋性毒性。GBM的异常特征改变了神经元网络功能，导致代谢易损和肿瘤周围组织过度兴奋，肿瘤利用这些特性即使在切除后也有利于自身生长。很明显，GBM和癫痫之间存在复杂的、动态的相互作用，促进了两种病理的进展。这种相互作用由于同时存在扩频去极化（SD）而变得更加复杂。gbm相关癫痫样活动和sd相关直流电（DC）转移的自发性、高频特性需要能够在宽带宽上记录大脑信号的技术，这对全面的电生理研究提出了重大挑战。这篇综述将首先详细研究促进GBM中网络高兴奋性的潜在机制。然后，我们将讨论如何从网络水平对这些病理进行调查，并利用新的电生理工具，将对gbm相关的癫痫发生产生更有效的临床相关理解。除此之外，我们将评估当前临床前研究的临床相关性，并考虑未来的治疗进展如何影响GBM、SDs和癫痫发作之间的双向关系。
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.
登录
查看更多内容
影响因子：
3
作者：
Brito da Silva, Anderson;Pennifold, Jane;Henley, Ben;Chatterjee, Koustav;Bateman, David;Whittaker, Roger W.;Joshi, Abhijit;Kumar, Hrishikesh;Nicholson, Claire;Baker, Mark R.;Greenhill, Stuart D.;Walsh, Richard;Seri, Stefano;Jones, Roland S. G.;Woodhall, Gavin L.;Cunningham, Mark O.
通讯作者：
Cunningham, Mark O.
影响因子：
4.9
作者：
Berger, M.;Speckmann, E-J;Gorji, A.
通讯作者：
Gorji, A.
影响因子：
4.6
作者：
Bronisz E;Kurkowska-Jastrzębska I
通讯作者：
Kurkowska-Jastrzębska I
影响因子：
2.2
作者：
Alvestad, Silje;Hammer, Janniche;Ottersen, Ole Petter
通讯作者：
Ottersen, Ole Petter
影响因子：
28.4
作者：
Brown TJ;Brennan MC;Li M;Church EW;Brandmeir NJ;Rakszawski KL;Patel AS;Rizk EB;Suki D;Sawaya R;Glantz M
通讯作者：
Glantz M