2‐Deoxy‐<scp>d</scp>‐glucose enhances tonic inhibition through the neurosteroid‐mediated activation of extrasynaptic <scp>GABA</scp><sub>A</sub> receptors

Forte, Nicola; Medrihan, Lucian; Cappetti, Barbara; Baldelli, Pietro; Benfenati, Fabio

doi:10.1111/epi.13578

Cited by 39 publications

(37 citation statements)

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“…A recent preliminary study reported that 2-DG reduces both spontaneous (and miniature) excitatory synaptic currents and spontane-ous inhibitory synaptic currents (Pan et al 2014), supporting this hypothesis. Also, a recent study in hippocampal dentate gyrus neurons showed that 2-DG enhanced tonic GABAergic current and reduced neuron excitability (Forte et al 2016). In addition, glycolytic inhibition may shift G-6-P into the pentose phosphate pathway (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Thus altering energy metabolism may represent a novel strategy and alternative therapy for seizure control, particularly for those resistant to drugs (Kawamura et al 2016). We and others previously proposed that direct inhibition of glycolysis leads to seizure control and that the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) produces acute anticonvulsant effects in vitro (Forte et al 2016;Stafstrom et al 2009) and chronic antiepileptic effects in vivo (Garriga-Canut et al 2006;Gasior et al 2010;Stafstrom et al 2009). Specifically, we previously showed that 2-DG decreases epileptiform activity induced by elevated extracellular potassium, 4-aminopyridine (4-AP), and bicuculline in brain slices from adult animals (Stafstrom et al 2009).…”

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confidence: 99%

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Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

Shao

Stafstrom

2017

Journal of Neurophysiology

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Neuronal activity is energy demanding and coupled to cellular metabolism. In this study, we investigated the effects of glycolytic inhibition with 2-deoxy-d-glucose (2-DG) on basal membrane properties, spontaneous neuronal firing, and epileptiform network bursts in hippocampal slices. The effect of glycolytic inhibition on basal membrane properties was examined in hippocampal CA1 neurons, which are not ordinarily active spontaneously. Intracellular application of 2-DG did not significantly alter the membrane input resistance, action-potential threshold, firing pattern, or input-output relationship of these neurons compared with simultaneously recorded neighboring neurons without intracellular 2-DG. The effect of glycolytic inhibition on neuronal firing was tested in spontaneously active hippocampal neurons (CA3) when synaptic transmission was left intact or blocked with AMPA, NMDA, and GABA receptor antagonists (DNQX, APV, and bicuculline, respectively). Under both conditions (synaptic activity intact or blocked), bath application of 2-DG (2 mM) blocked spontaneous firing in ~2/3 (67 and 71%, respectively) of CA3 pyramidal neurons. In contrast, neuronal firing of CA3 neurons persisted when 2-DG was applied intracellularly, suggesting that glycolytic inhibition of individual neurons is not sufficient to stop neuronal firing. The effects of 2-DG on epileptiform network bursts in area CA3 were tested in Mg-free medium containing 50 µM 4-aminopyridine. Bath application of 2-DG abolished these epileptiform bursts in a dose-dependent and all-or-none manner. Taken together, these data suggest that altered glucose metabolism profoundly affects cellular and network hyperexcitability and that glycolytic inhibition by 2-DG can effectively abrogate epileptiform activity. Neuronal activity is highly energy demanding and coupled to cellular metabolism. In this study, we demonstrate that glycolytic inhibition with 2-deoxy-d-glucose (2-DG) effectively suppresses spontaneous neuronal firing and epileptiform bursts in hippocampal slices. These data suggest that an altered metabolic state can profoundly affect cellular and network excitability, and that the glycolytic inhibitor 2-DG may hold promise as a novel treatment of drug-resistant epilepsy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

Shao

Stafstrom

2017

Journal of Neurophysiology

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“…Elevated GABAergic activity leads to increased extracellular potassium, which supports hyperexcitability and epileptiform synchronization (Zuckermann and Glaser, 1968;Fertziger and Ranck, 1970;de Curtis and Gnatkovsky, 2009). On the other hand, there are studies suggesting that the impaired GABAergic inhibition, related to a selective loss of inhibitory interneurons, accounts for epileptiform activity (Wendling et al, 2002;Forte et al, 2016). Although electrophysiological validations are required, it is tempting to speculate that the normalization of GABAergic transmission by GDNF prevents the broad spatial hypersynchronous recruitment of neurons and interneurons observed at the transition from interictal to ictal activity (Schevon et al, 2012;Fujita et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Long-Term, Targeted Delivery of GDNF from Encapsulated Cells Is Neuroprotective and Reduces Seizures in the Pilocarpine Model of Epilepsy

et al. 2019

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Neurotrophic factors are candidates for treating epilepsy, but their development has been hampered by difficulties in achieving stable and targeted delivery of efficacious concentrations within the desired brain region. We have developed an encapsulated cell technology that overcomes these obstacles by providing a targeted, continuous, de novo synthesized source of high levels of neurotrophic molecules from human clonal ARPE-19 cells encapsulated into hollow fiber membranes. Here we illustrate the potential of this approach for delivering glial cell line-derived neurotrophic factor (GDNF) directly to the hippocampus of epileptic rats. In vivo studies demonstrated that bilateral intrahippocampal implants continued to secrete GDNF that produced high hippocampal GDNF tissue levels in a long-term manner. Identical implants robustly reduced seizure frequency in the pilocarpine model. Seizures were reduced rapidly, and this effect increased in magnitude over 3 months, ultimately leading to a reduction of seizures by 93%. This effect persisted even after device removal, suggesting potential disease-modifying benefits. Importantly, seizure reduction was associated with normalized changes in anxiety and improved cognitive performance. Immunohistochemical analyses revealed that the neurological benefits of GDNF were associated with the normalization of anatomical alterations accompanying chronic epilepsy, including hippocampal atrophy, cell degeneration, loss of parvalbumin-positive interneurons, and abnormal neurogenesis. These effects were associated with the activation of GDNF receptors. All in all, these results support the concept that the implantation of encapsulated GDNF-secreting cells can deliver GDNF in a sustained, targeted, and efficacious manner, paving the way for continuing preclinical evaluation and eventual clinical translation of this approach for epilepsy.Epilepsy is one of the most common neurological conditions, affecting millions of individuals of all ages. These patients experience debilitating seizures that frequently increase over time and can associate with significant cognitive decline and psychiatric disorders that are generally poorly controlled by pharmacotherapy. We have developed a clinically validated, implantable cell encapsulation system that delivers high and consistent levels of GDNF directly to the brain. In epileptic animals, this system produced a progressive and permanent reduction (Ͼ90%) in seizure frequency. These benefits were accompanied by improvements in cognitive and anxiolytic behavior and the normalization of changes in CNS anatomy that underlie chronic epilepsy. Together, these data suggest a novel means of tackling the frequently intractable neurological consequences of this devastating disorder.

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“…49 In addition to its effects on excitatory synaptic transmission, 2DG may also affect GABAergic signaling, specifically by potentiating extrasynaptic tonic GABAergic current through activation of neurosteroidogenesis. 53 However, unlike glutamate in excitatory neurotransmission, GABA does not couple inhibitory neuronal activity with glucose utilization. 54 Thus, although 2DG may increase postsynaptic tonic inhibition, this action appears independent of its effect on glycolysis.…”

Section: Potential Mechanisms Of 2dg Actionmentioning

confidence: 99%

Glycolytic inhibition: A novel approach toward controlling neuronal excitability and seizures

2018

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SUMMARYConventional antiseizure medications reduce neuronal excitability through effects on ion channels or synaptic function. In recent years, it has become clear that metabolic factors also play a crucial role in the modulation of neuronal excitability. Indeed, metabolic regulation of neuronal excitability is pivotal in seizure pathogenesis and control. The clinical effectiveness of a variety of metabolism-based diets, especially for children with medication-refractory epilepsy, underscores the applicability of metabolic approaches to the control of seizures and epilepsy. Such diets include the ketogenic diet, the modified Atkins diet, and the low-glycemic index treatment (among others). A promising avenue to alter cellular metabolism, and hence excitability, is by partial inhibition of glycolysis, which has been shown to reduce seizure susceptibility in a variety of animal models as well as in cellular systems in vitro. One such glycolytic inhibitor, 2-deoxy-D-glucose (2DG), increases seizure threshold in vivo and reduces interictal and ictal epileptiform discharges in hippocampal slices. Here, we review the role of glucose metabolism and glycolysis on neuronal excitability, with specific reference to 2DG, and discuss the potential use of 2DG and similar agents in the clinical arena for seizure management.

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2‐Deoxy‐d‐glucose enhances tonic inhibition through the neurosteroid‐mediated activation of extrasynaptic GABA_A receptors

Abstract: We demonstrated, for the first time, that 2-DG potentiates the extrasynaptic tonic GABAergic current through activation of neurosteroidogenesis. Such tonic inhibition represents the main conductance responsible for the antiseizure action of this glycolytic inhibitor.

Cited by 39 publications

References 41 publications

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

Long-Term, Targeted Delivery of GDNF from Encapsulated Cells Is Neuroprotective and Reduces Seizures in the Pilocarpine Model of Epilepsy

Glycolytic inhibition: A novel approach toward controlling neuronal excitability and seizures

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2‐Deoxy‐d‐glucose enhances tonic inhibition through the neurosteroid‐mediated activation of extrasynaptic GABAA receptors

Abstract: We demonstrated, for the first time, that 2-DG potentiates the extrasynaptic tonic GABAergic current through activation of neurosteroidogenesis. Such tonic inhibition represents the main conductance responsible for the antiseizure action of this glycolytic inhibitor.

Cited by 39 publications

References 41 publications

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

Glycolytic inhibition by 2-deoxy-d-glucose abolishes both neuronal and network bursts in an in vitro seizure model

Long-Term, Targeted Delivery of GDNF from Encapsulated Cells Is Neuroprotective and Reduces Seizures in the Pilocarpine Model of Epilepsy

Glycolytic inhibition: A novel approach toward controlling neuronal excitability and seizures

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2‐Deoxy‐d‐glucose enhances tonic inhibition through the neurosteroid‐mediated activation of extrasynaptic GABA_A receptors