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

Shao, Li; Stafstrom, Carl E.

doi:10.1152/jn.00100.2017

Cited by 31 publications

(36 citation statements)

References 45 publications

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“…The effects of 2DG on epileptiform network bursts in area CA3 were also tested in Mg 2+ ‐free medium containing 4‐AP. Bath application of 2DG abolished these epileptiform bursts in a dose‐dependent, all‐or‐none manner . Taken together, these data suggest that altered glucose metabolism profoundly affects cellular and network hyperexcitability and that glycolytic inhibition by 2DG can effectively abate epileptiform activity.…”

Section: Dg Exerts Antiseizure Actions In Vitro and In Vivomentioning

confidence: 68%

“…Bath application of 2DG abolished these epileptiform bursts in a dose-dependent, all-or-none manner. 23 Taken together, these data suggest that altered glucose metabolism profoundly affects cellular and network hyperexcitability and that glycolytic inhibition by 2DG can effectively abate epileptiform activity. In summary, 2DG has an antiseizure effect on both interictal and ictal epileptiform activity in the hippocampal CA3 region.…”

Section: Glycolysis Inhibition-a Novel Approach To Seizure Controlmentioning

confidence: 78%

“…2DG also reduces the frequency of spontaneous inhibitory postsynaptic current (sIPSC) when K 0 + is elevated (7.5 mM), but to a lesser extent than sEPSCs, resulting in an overall decrease in excitatory neurotransmission . 2DG does not affect intrinsic membrane properties significantly, and its acute effects on synaptic transmission appear to be primarily presynaptic . In a 4‐AP model of neocortical seizures, 2DG reduced the amplitude and duration of seizures over minutes to an hour; this slower action could be related to cell death secondary to glycolytic inhibition …”

Section: Potential Mechanisms Of 2dg Actionmentioning

confidence: 97%

“…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 alpha-amino-3hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), N-methyl-D-aspartate (NMDA), and GABA A receptor antagonists (6,7-dinitroquinoxaline-2,3-dione (DNQX), 2amino-5-phosphonovalerate (APV), and bicuculline, respectively). 23 Under both conditions (synaptic activity intact or blocked), bath application of 2DG inhibited spontaneous firing in 67% of CA3 pyramidal neurons. In contrast, CA3 neuronal firing persisted when 2DG was applied intracellularly, suggesting that glycolytic inhibition of individual neurons is not sufficient to stop neuronal firing.…”

Section: Glycolysis Inhibition-a Novel Approach To Seizure Controlmentioning

confidence: 97%

“…In slices from immature animals (postnatal days 10–13 [P10–13]), 7.5 mM K 0 + induced prolonged ictal discharges in the CA3 subfield for 10–30 s; 2DG decreased the ictal burst frequency. 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 alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazoleproprionic acid (AMPA), N ‐methyl‐ d ‐aspartate (NMDA), and GABA A receptor antagonists (6,7‐dinitroquinoxaline‐2,3‐dione (DNQX), 2‐amino‐5‐phosphonovalerate (APV), and bicuculline, respectively) . Under both conditions (synaptic activity intact or blocked), bath application of 2DG inhibited spontaneous firing in 67% of CA3 pyramidal neurons.…”

Section: Dg Exerts Antiseizure Actions In Vitro and In Vivomentioning

confidence: 99%

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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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Section: Dg Exerts Antiseizure Actions In Vitro and In Vivomentioning

confidence: 68%

Section: Glycolysis Inhibition-a Novel Approach To Seizure Controlmentioning

confidence: 78%

Section: Potential Mechanisms Of 2dg Actionmentioning

confidence: 97%

Section: Glycolysis Inhibition-a Novel Approach To Seizure Controlmentioning

confidence: 97%

Section: Dg Exerts Antiseizure Actions In Vitro and In Vivomentioning

confidence: 99%

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

2018

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Glycolytic lactate production supports status epilepticus in experimental animals

Skwarzynska,

Sun,

Kasprzak

et al. 2023

Ann Clin Transl Neurol

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ObjectiveStatus epilepticus (SE) requires rapid intervention to prevent cerebral injury and mortality. The ketogenic diet, which bypasses glycolysis, is a promising remedy for patients with refractory SE. We tested the role of glycolytic lactate production in sustaining SE.MethodsExtracellular lactate and glucose concentration during a seizure and SE in vivo was measured using lactate and glucose biosensors. A lactate dehydrogenase inhibitor, oxamate, blocked pyruvate to lactate conversion during SE. Video‐EEG recordings evaluated seizure duration, severity, and immunohistochemistry was used to determine neuronal loss. Genetically encoded calcium indicator GCaMP7 was used to study the effect of oxamate on CA1 pyramidal neurons in vitro. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded from CA1 neurons to study oxamate's impact on neurotransmission.ResultsThe extracellular glucose concentration dropped rapidly during seizures, and lactate accumulated in the extracellular space. Inhibition of pyruvate to lactate conversion with oxamate terminated SE in mice. There was less neuronal loss in treated compared to control mice. Oxamate perfusion decreased tonic and phasic neuronal activity of GCaMP7‐expressing CA1 pyramidal neurons in vitro. Oxamate application reduced the frequency, but not amplitude of sEPSCs recorded from CA1 neurons, suggesting an effect on the presynaptic glutamatergic neurotransmission.InterpretationA single seizure and SE stimulate lactate production. Diminishing pyruvate to lactate conversion with oxamate terminated SE and reduced associated neuronal death. Oxamate reduced neuronal excitability and excitatory neurotransmission at the presynaptic terminal. Glycolytic lactate production sustains SE and is an attractive therapeutic target.

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2‐deoxyglucose and β‐hydroxybutyrate fail to attenuate seizures in the betamethasone‐NMDA model of infantile spasms

2021

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Infantile spasms (IS) is an epileptic encephalopathy with a poor neurodevelopmental prognosis, and limited, often ineffective treatment options. The effectiveness of metabolic approaches to seizure control is being increasingly shown in a wide variety of epilepsies. This study investigates the efficacy of the glycolysis inhibitor 2-deoxyglucose (2-DG) and the ketone body β-hydroxybutyrate (BHB) in the betamethasone-NMDA model of rat IS. Prenatal rats were exposed to betamethasone on gestational day 15 (G15) and NMDA on postnatal day 15 (P15). Video-electroencephalography (v-EEG) was used to monitor spasms. NMDA consistently induced hyperflexion spasms associated with interictal sharp-slow wave EEG activity and ictal flattening of EEG signals, reminiscent of hypsarrhythmia and electrodecrement, respectively. 2-DG (500 mg/kg, i.p), BHB (200 mg/kg, i.p.), or both were administered immediately after occurrence of the first spasm. No experimental treatment altered significantly the number, severity, or progression of spasms compared with saline treatment. These data suggest that metabolic inhibition of glycolysis or ketogenesis does not reduce infantile spasms in the NMDA model. The study further validates the betamethasone-NMDA model in terms of its behavioral and electrographic resemblance to human IS and supports its use for preclinical drug screening.

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

Cited by 31 publications

References 45 publications

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

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

Glycolytic lactate production supports status epilepticus in experimental animals

2‐deoxyglucose and β‐hydroxybutyrate fail to attenuate seizures in the betamethasone‐NMDA model of infantile spasms

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