Sorbonne University, UPMC University Paris 06, F-75005 Paris, France.
Neurophysiology Department, UPMC, Centre Hospitalo-Universitaire Pitié-Salpêtrière, APHP, F-75013 Paris, France.
Nat Rev Neurol. 2016 Apr;12(4):204-16. doi: 10.1038/nrneurol.2016.26. Epub 2016 Mar 11.
Epilepsy often develops in patients with glioma, and the two conditions share common pathogenic mechanisms. Altered expression of glutamate transporters, including the cystine-glutamate transporter (xCT) system, increases concentrations of extracellular glutamate, which contribute to epileptic discharge, tumour proliferation and peripheral excitotoxicity. Furthermore, mutation of the isocitrate dehydrogenase 1 gene in low-grade gliomas causes production of D-2-hydroxyglutarate, a steric analogue of glutamate. Dysregulation of intracellular chloride promotes glioma cell mitosis and migration, and γ-aminobutyric acid (GABA) signalling suppresses proliferation. In neurons, however, chloride accumulation leads to aberrant depolarization on GABA receptor activation, thereby promoting epileptic activity. The molecular target of rapamycin (mTOR) pathway and epigenetic abnormalities are also involved in the development of tumours and seizures. Antitumour therapy can contribute to seizure control, and antiepileptic drugs might have beneficial effects on tumours. Symptomatic treatment with antiepileptic drugs carries risks of adverse effects and drug interactions. In this Review, we discuss the potential for single therapeutic agents, such as the xCT blocker sulfasalazine, the chloride regulator bumetanide, and the histone deacetylase inhibitor valproic acid, to manage both gliomas and associated epilepsy. We also provide guidance on the evidence-based use of antiepileptic drugs in brain tumours. The development of solo therapies to treat both aspects of gliomas promises to yield more-effective treatment with fewer risks of toxicity and drug interactions.
癫痫常发生于脑胶质瘤患者，两者具有共同的发病机制。谷氨酸转运体（包括胱氨酸-谷氨酸转运体[xCT]系统）表达改变，导致细胞外谷氨酸浓度增加，进而引发癫痫发作、肿瘤增殖和外周兴奋性毒性。此外，低级别胶质瘤中异柠檬酸脱氢酶 1 基因的突变导致 D-2-羟戊二酸的产生，这是谷氨酸的立体异构体。细胞内氯离子的失调促进了胶质瘤细胞的有丝分裂和迁移，而γ-氨基丁酸（GABA）信号通路抑制增殖。然而，在神经元中，氯离子的积累导致 GABA 受体激活时出现异常去极化，从而促进癫痫活动。雷帕霉素（mTOR）通路的分子靶标和表观遗传异常也参与了肿瘤和癫痫的发生。抗肿瘤治疗有助于控制癫痫发作，抗癫痫药物可能对肿瘤有有益的影响。抗癫痫药物的对症治疗存在不良反应和药物相互作用的风险。在这篇综述中，我们讨论了单一治疗药物的潜力，如 xCT 阻断剂柳氮磺胺吡啶、氯离子调节剂布美他尼和组蛋白去乙酰化酶抑制剂丙戊酸，以同时管理脑肿瘤及其相关癫痫。我们还就抗癫痫药物在脑肿瘤中的循证应用提供了指导。开发单独治疗这两方面的疗法有望产生更有效的治疗方法，同时减少毒性和药物相互作用的风险。
