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• W2316198248 abstract "Patients with primary infiltrative brain tumors frequently have seizures, with epilepsy rates ranging from 60% to 100% in patients with low-grade gliomas and 25% to 60% in patients with high-grade gliomas.1,2 Several studies have demonstrated that an imbalance between excitatory glutamatergic and inhibitory gamma-aminobutyric acid (GABA)ergic activity may underlie epileptic activity, with excess glutamate release contributing to neuronal death in high-grade tumors.3 GABAA receptor expression and synapses are known to be reduced in peritumoral neocortical cells.4 Furthermore, research on nontumoral mesial temporal sclerosis tissue has implicated pathological GABAergic signaling in human epileptogenesis. The K+-Cl− cotransporter NKCC1, which transports chloride ions into the cell, is normally expressed at low levels in adult human cerebral tissue, whereas the KCC2 cotransporter, which extrudes chloride ions, is normally expressed at high levels. Decreased neuronal expression of KCC2 in epileptogenic tissue results in increased intracellular chloride. This perturbation in neuronal chloride homeostasis converts GABAA receptor activation from the normal adult brain hyperpolarizing inhibitory response to a depolarizing excitatory response (Figure 1).5 A similar mechanism of increased intracellular chloride has also been implicated in promoting glioma cell migration.6 Recently, 2 studies investigated the role of chloride homeostasis and GABAergic signaling in peritumoral epileptogenesis using human neocortical slices7 and a mouse glioma model,8 respectively.Figure 1: Glutamatergic and inhibitory gamma-aminobutyric acid (GABA)--induced epileptiform discharge with increased intracellular chloride (A) and GABAergic depolarization in normal pyramidal cell (B). Adapted from Holmes et al.9 (Reprinted from Handbook of Clinical Neurology, Vol 107, Holmes GL, Milh MD, Dulac O, Maturation of the human brain and epilepsy, Pages No. 135-143, Copyright [2012], with permission from Elsevier.)In human peritumoral neocortical slices, Pallud et al7 from the University of Paris Sorbonne demonstrated that GABAergic perturbations in peritumoral tissue from both low- and high-grade gliomas contribute to epileptogenicity. Peritumoral specimens exhibited interictal-like discharges, peri-ictal discharges (PIDs), and ictal-like discharges (IDs), whereas control and tumor tissue did not. The authors found that interictal-like discharges were suppressed by inhibition of both glutamatergic AMPA and GABAA receptors, identifying the role of both neurotransmitters in the generation of these discharges. Furthermore, researchers demonstrated that GABAA alone can depolarize pyramidal cells and does so at a significantly higher rate in peritumoral tissue than normal tissue. Consistent with prior human epilepsy work,5 the authors hypothesized that abnormal cellular Cl− trafficking was responsible. They found that peritumoral pyramidal neurons from epileptogenic tissue expressed increased NKCC1 levels relative to normal tissue and abnormally decreased KCC2 receptor levels (Figure 2), resulting in elevated intracellular chloride. GABA activation of neurons with elevated intracellular chloride induces excitatory depolarization rather than the inhibitory neuronal hyperpolarization that is normally seen in the adult brain in response to GABAA activation (Figure 1).Figure 2: KCC2 immunoreactivity in peritumoral vs control neurons. In contrast to expression in control neurons, KCC2 expression is both decreased and mislocalized from the cell membrane to the cytoplasm in peritumoral epileptogenic neurons. Adapted from Figure 4 of Pallud et al.7 (From Pallud J, Le Van Quyen M, Bielle F, et al. Cortical GABAergic excitation contributes to epileptic activities around human glioma. Sci Transl Med. 2014;6(244):244ra89. Reprinted with permission from AAAS.)The Haberfeld team went on to further clarify the complex pathological interplay that characterizes human peritumoral epilepsy. To examine activity more closely resembling a true seizure, they induced IDs by placing tissues in a proconvulsant environment, allowing the recording of PIDs. PIDs always preceded IDs and increased in frequency during the transition to IDs. However, PIDs were not affected by GABA antagonists. In addition, chloride blockade via NKCC1 cotransporter antagonism abolished interictal-like discharges and IDs but had no influence on the firing of PIDs. During the transition to IDs, PIDs from different foci tended to increase in synchrony, and conduction speed increased. Thus, PIDs appear to contribute to intracellular Cl− accumulation through recurrent, synchronous activation of pyramidal cells, whereas GABAergic interneurons responsible for interictal-like discharges actually depolarize the pyramidal cells themselves. In a separate study using a mouse glioma model, Campbell et al8 from the Sontheimer laboratory at the University of Alabama Birmingham further characterized the interplay between GABAergic excitation and their prior findings of peritumoral pathological glutamate. This laboratory has previously shown through a series of studies that the excitatory amino acid neurotransmitter glutamate (Glu) accumulates in peritumoral tissue via release from gliomas by the “system xc” (SXC) cystine-glutamate antiporter. Pathological levels of extracellular glutamate likely promote epileptogenicity and tumor growth. In a recent study published in Glia, human glioblastoma multiforme--derived xenograft tumors were injected into adult C.B.17 scid mice, creating a mouse tumor model with spontaneous seizures. Peritumoral tissue exhibited decreased GABAergic inhibition resulting from a combination of fewer GABAergic interneurons and decreased KCC2 cotransporter expression in peritumoral neurons. Similar to the human study discussed above, elevated intracellular chloride, with a depolarizing GABA response, was found in peritumoral neurons. Importantly, whereas GABAergic depolarization occurred independently of glutamate release, epileptic activity was present only in tissue with decreased GABAergic inhibition and decreased SXC expression. Taken together, these provocative studies provide evidence that epileptogenicity in peritumoral tissue results from both pathological glutamate release and GABA-mediated disinhibition of surrounding pyramidal cells. Interestingly, many features of peritumoral epileptiform activity described in these articles are similar to features of nontumoral human epilepsy, suggesting a convergence of pathological mechanisms. These findings potentially have widespread applicability to antiepileptic and antitumor drug development and delivery. Drugs that target cellular membrane K+-Cl− cotransporters and delivery mechanisms aimed at delivering these drugs specifically to peritumoral tissue represent possible clinical and technological patient treatment advances that could both improve seizure control and promote survival in glioma patients." @default.
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• W2316198248 date "2014-12-01" @default.
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• W2316198248 title "Why Glioma Patients Seize" @default.
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• W2316198248 doi "https://doi.org/10.1227/01.neu.0000457190.56416.e6" @default.
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