title: Seizures and gliomas--towards a single therapeutic approach.
abstract: 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.
authors.affiliation: Sorbonne University, UPMC University Paris 06, F-75005 Paris, France.|Neurophysiology Department, UPMC, Centre Hospitalo-Universitaire Pitié-Salpêtrière, APHP, F-75013 Paris, France.|INSERM U1129 "Infantile Epilepsies and Brain Plasticity", Paris, France; Paris Descartes University, PRES Sorbonne Paris Cité; CEA, Gif sur Yvette, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Huberfeld
authors.affiliation: Service de Neuro-oncologie Mazarin, UPMC, Centre Hospitalo-Universitaire Pitié-Salpêtrière, APHP, F-75013 Paris, France.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Vecht
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000150:complications* / Q000175:diagnosis / Q000628:therapy*; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism; D005910:Glioma / Q000150:complications* / Q000175:diagnosis / Q000628:therapy*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D012640:Seizures / Q000150:complications* / Q000175:diagnosis / Q000628:therapy*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D018698:Glutamic Acid; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases