Pathogenesis of glioma-associated epilepsy and its therapy

WANG Xinxin; LU Qinchi

doi:10.12022/jnnr.2016-0058

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Journal of Neurology and Neurorehabilitation ›› 2016, Vol. 12 ›› Issue (4) : 208-214. DOI: 10.12022/jnnr.2016-0058

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Pathogenesis of glioma-associated epilepsy and its therapy

WANG Xinxin, LU Qinchi

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Abstract

Epilepsy can be developed in 30%-50% of the patients with glioma, which is the most common form of brain tumors. The seizures induced by glioma are still remained after resection of glioma lesions, therefore it is essential and meaningful to explore the pathogenesis and the related treatment of glioma-associated epilepsy. This paper discusses the pathogenic mechanisms involved in the development of glioma-associated epilepsy, including the alteration of glutamate and its transporters, the dysregulation of intracellular chloride (Cl)^-, the alteration of gamma-amino butyric acid (GABA) signal pathway-mediated inhibitory effect, and the abnormalities in mammalian target of rapamycin (mTOR) signal pathway. The related drugs based on the pathogenic mechanisms of glioma-associated epilepsy are summarized, such as sulfasalazine—the blocker of cystine-glutamate transporter (xCT), bumetanide—the regulator for Cl^-, and rapamycin which is an inhibitor of mTOR, in order to provide effective treatment strategies for glioma-associated epilepsy. Finally, the guidance about the use of anti-epileptic drugs (AEDs) in controlling the glioma-associated seizures is also summarized.

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Glioma / Epilepsy / Pathogenesis / Therapy

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WANG Xinxin, LU Qinchi. Pathogenesis of glioma-associated epilepsy and its therapy[J]. Journal of Neurology and Neurorehabilitation. 2016, 12(4): 208-214 https://doi.org/10.12022/jnnr.2016-0058

References

[1] YUEN T I, MOROKOFF A P, BJORKSTEN A, et al.Glutamate is associated with a higher risk of seizures in patients with gliomas[J]. Neurology, 2012, 79(9):883-889.
[2] IUCHI T, HASEGAWA Y, KAWASAKI K, et al.Epilepsy in patients with gliomas: incidence and control of seizures[J]. J Clin Neurosci, 2015, 22(1):87-91.
[3] VAN BREEMEN M S, WILMS E B, VECHT C J. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management[J]. Lancet Neurol, 2007, 6(5):421-430.
[4] CASCINO G D.Epilepsy and brain tumors: implications for treatment[J]. Epilepsia, 1990, 31(Suppl 3):S37-S44.
[5] RATHORE C, THOMAS B, KESAVADAS C, et al.Seizure characteristics and prognostic factors of gliomas[J]. Epilepsia, 2013, 54(9):12-17.
[6] TAPHOORN M J.Neurocognitive sequelae in the treatment of low-grade gliomas[J]. Semin Oncol, 2003, 30(6):45-48.
[7] KÖHLING R, SENNER V, PAULUS W, et al. Epileptiform activity preferentially arises outside tumor invasion zone in glioma xenotransplants[J]. Neurobiol Dis, 2006, 22(1):64-75.
[8] BEAUMONT A, WHITTLE I R.The pathogenesis of tumour associated epilepsy[J]. Acta Neurochir (Wien), 2000,142(1):1-15.
[9] MARCUS H J, CARPENTER K L, PRICE S J, et al.In vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines[J]. J Neurooncol, 2010, 97(1):11-23.
[10] YE Z C, ROTHSTEIN J D, SONTHEIMER H.Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange[J]. J Neurosci, 1999, 19(24):10767-10777.
[11] TAKANO T, LIN J H, ARCUINO G, et al.Glutamate release promotes growth of malignant gliomas[J]. Nat Med, 2001, 7(9):1010-1015.
[12] SHAMJI M F, FRIC-SHAMJI E C, BENOIT B. Brain tumors and epilepsy: pathophysiology of peritumoral changes[J]. Neurosurg Rev, 2009, 32(3):275-284.
[13] KANDIL S, BRENNAN L, MCBEAN G J.Glutathione depletion causes a JNK and p38MAPK-mediated increase in expression of cystathionine-gamma-lyase and upregulation of the transsulfuration pathway in C6 glioma cells[J]. Neurochem Int, 2010, 56(4):611-619.
[14] BUCKINGHAM S C, ROBEL S.Glutamate and tumor-associated epilepsy: glial cell dysfunction in the peritumoral environment[J]. Neurochem Int, 2013, 63(7):696-701.
[15] STOCKHAMMER F, MISCH M, HELMS H J, et al.IDH1/2 mutations in WHO grade II astrocytomas associated with localization and seizure as the initial symptom[J]. Seizure, 2012, 21(3):194-197.
[16] SANSON M, MARIE Y, PARIS S, et al.Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas[J]. J Clin Oncol, 2009, 27(25):4150-4154.
[17] ROBERT S M, BUCKINGHAM S C, CAMPBELL S L, et al.SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma[J]. Sci Transl Med, 2015, 7(289):286-289.
[18] WANG Z F, CHEN H L.Relationship between IDH1 mutation and preoperative seizure in low-grade gliomas: A meta-analysis[J]. Clin Neurol Neurosurg, 2016, 148:79-84.
[19] ZOU Y, BAI H X, WANG Z, et al.Association of IDH1/2 mutation with preoperative seizure in low-grade gliomas: how strong is the evidence[J]. Epilepsy Res, 2015, 112:154-155.
[20] HAGLUND M M, BERGER M S, KUNKEL D D, et al.Changes in gamma-aminobutyric acid and somatostatin in epileptic cortex associated with low-grade gliomas[J]. J Neurosurg, 1992, 77(2):209-216.
[21] MARCO P, SOLA R G, RAMÓN Y CAJAL S, et al. Loss of inhibitory synapses on the soma and axon initial segment of pyramidal cells in human epileptic peritumoural neocortex: implications for epilepsy[J]. Brain Res Bull, 1997, 44(1):47-66.
[22] HAAS B R, SONTHEIMER H.Inhibition of the Sodium-Potassium-Chloride Cotransporter Isoform-1 reduces glioma invasion[J]. Cancer Res, 2010, 70(13):5597-5606.
[23] MUÑOZ A, MÉNDEZ P, DEFELIPE J, et al. Cation-chloride cotransporters and GABA-ergic innervation in the human epileptic hippocampus[J]. Epilepsia, 2007, 48(4):663-673.
[24] PALMA E, AMICI M, SOBRERO F, et al.Anomalous levels of Cl^– transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory[J]. Proc Natl Acad Sci U S A, 2006, 103(22):8465-8468.
[25] COULL J A, BEGGS S, BOUDREAU D, et al.BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain[J]. Nature, 2005, 438(7070):1017-1021.
[26] LEE H H, DEEB T Z, WALKER J A, et al.NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents[J]. Nat Neurosci, 2011, 14(6):736-743.
[27] LIPTON J O, SAHIN M.The neurology of mTOR[J]. Neuron, 2014, 84(2):275-291.
[28] BATEUP H S, JOHNSON C A, DENEFRIO C L, et al.Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis[J]. Neuron, 2013, 78(3):510-522.
[29] EPI4K CONSORTIUM, EPILEPSY PHENOME/GENOME PROJECT, ALLEN A S, et al. De novo mutations in epileptic encephalopathies[J]. Nature, 2013, 501(7466):217-221.
[30] PRABOWO A S, IYER A M, VEERSEMA T J, et al.BRAF V600E mutation is associated with mTOR signaling activation in glioneuronal tumors[J]. Brain Pathol, 2014, 24(1):52-66.
[31] BUCKINGHAM S C, CAMPBELL S L, HAAS B R, et al.Glutamate release by primary brain tumors induces epileptic activity[J]. Nat Med, 2011, 17(10):1269-1274.
[32] ISHIUCHI S, YOSHIDA Y, SUGAWARA K, et al.Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation[J]. J Neurosci, 2007, 27(30):7987-8001.
[33] YOHAY K, TYLER B, WEAVER K D, et al.Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models[J]. J Neurosurg, 2014, 120(4):854-863.
[34] CHING J, AMIRIDIS S, STYLLI S S, et al.The peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells[J]. Oncotarget, 2015, 6(25):21301-21314.
[35] SAHA L, BHANDARI S, BHATIA A, et al.Anti-kindling effect of bezafibrate, a peroxisome proliferator-activated receptors alpha agonist, in pentylenetetrazole induced kindling seizure model[J]. J Epilepsy Res, 2014, 4(2):45-54.
[36] ROHLE D, POPOVICI-MULLER J, PALASKAS N, et al.An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells[J]. Science, 2013, 340(6132):626-630.
[37] RHEIMS S, REPRESA A, BEN-ARI Y, et al.Layer-specific generation and propagation of seizures in slices of developing neocortex: role of excitatory GABAergic synapses[J]. J Neurophysiol, 2008, 100(2):620-628.
[38] NARDOU R, YAMAMOTO S, CHAZAL G, et al.Neuronal chloride accumulation and excitatory GABA underlie aggravation of neonatal epileptiform activities by phenobarbital[J]. Brain, 2011, 134(4):987-1002.
[39] HUBERFELD G, WITTNER L, CLEMENCEAU S, et al.Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy[J]. J Neurosci, 2007, 27(37):9866-9873.
[40] LYKKE K, TÖLLNER K, FEIT P W, et al. The search for NKCC1-selective drugs for the treatment of epilepsy: Structure-function relationship of bumetanide and various bumetanide derivatives in inhibiting the human cation-chloride cotransporter NKCC1A[J]. Epilepsy Behav, 2016, 59:42-49.
[41] HAMIDI S, AVOLI M.KCC2 function modulates in vitro ictogenesis[J]. Neurobiol Dis, 2015, 79:51-58.
[42] ZENG L H, XU L, GUTMANN D H, et al.Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex[J]. Ann Neurol, 2008, 63(4):444-453.
[43] KRUEGER D A, WILFONG A A, HOLLAND-BOULEY K, et al.Everolimus treatment of refractory epilepsy in tuberous sclerosis complex[J]. Ann Neurol, 2013, 74(5):679-687.
[44] CARDAMONE M, FLANAGAN D, MOWAT D, et al.Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex[J]. J Pediatr, 2014, 164(5):1195-1200.
[45] KRUMHOLZ A, WIEBE S, GRONSETH G S, et al.Evidence-based guideline: Management of an unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society[J]. Neurology, 2015, 84(16):1705-1713.
[46] WICK W, MENN O, MEISNER C, et al.Pharmacotherapy of epileptic seizures in glioma patients: who, when, why and how long[J]. Onkologie, 2005, 28(8-9):391-396.
[47] VECHT C J, KERKHOF M, DURAN-PENA A.Seizure prognosis in brain tumors: new insights and evidence-based management[J]. Oncologist, 2014, 19(7):751-759.
[48] BRODIE M J, SILLS G J.Combining antiepileptic drugs—rational polytherapy[J]. Seizure, 2011, 20(5):369-375.