Opposing effects of 2-deoxy-D-glucose on interictal- and ictal-like activity when K⁺ currents and GABA_A receptors are blocked in rat hippocampus in vitro

TY - JOUR

T1 - Opposing effects of 2-deoxy-D-glucose on interictal- and ictal-like activity when K+ currents and GABAA receptors are blocked in rat hippocampus in vitro

AU - Nedergaard, Steen Torben

AU - Andreasen, Mogens

PY - 2018

Y1 - 2018

N2 - The ketogenic diet (KD), a high-fat, carbohydrate-restricted diet, is used as an alternative treatment for drug-resistant epileptic patients. Evidence suggests that compromised glucose metabolism has a significant role in the anticonvulsant action of the KD; however, it is unclear what part of the glucose metabolism that is important. The present study investigates how selective alterations in glycolysis and oxidative phosphorylation influence epileptiform activity induced by blocking K + currents and GABAA and NMDA receptors in the hippocampal slice preparation. Blocking glycolysis with the glucose derivative 2-deoxy-D-glucose (2-DG; 10 mM) gave a fast reduction of the frequency of interictal discharge (IED) consistent with findings in other in vitro models. However, this was followed by the induction of seizure-like discharges in area CA1 and CA3. Substituting glucose with sucrose (glucopenia) had effects similar to those of 2-DG, whereas substitution with L-lactate or pyruvate reduced the IED but had a less proconvulsant effect. Blockade of ATP-sensitive K + channels, glycine or adenosine 1 receptors, or depletion of the endogenous anticonvulsant compound glutathione did not prevent the actions of 2-DG. Baclofen (2 μM) reproduced the effect of 2-DG on IED activity. The proconvulsant effect of 2-DG could be reproduced by blocking the oxidative phosphorylation with the complex I toxin rotenone (4 μM). The data suggest that inhibition of IED, induced by 2-DG and glucopenia, is a direct consequence of impairment of glycolysis, likely exerted via a decreased recurrent excitatory synaptic transmission in area CA3. The accompanying proconvulsant effect is caused by an excitatory mechanism, depending on impairment of oxidative phosphorylation. NEW & NOTEWORTHY This study reveals two opposing effects of 2-deoxy-D-glucose (2-DG) and glucopenia on in vitro epileptiformdischarge observed during combined blockade of K + currents andGABA A receptors. Interictal-like activity is inhibited by a mechanismthat selectively depends on impairment of glycolysis and that resultsfrom a decrease in the strength of excitatory recurrent synaptictransmission in area CA3. In contrast, 2-DG and glucopenia facilitateictal-like activity by an excitatory mechanism, depending on impairmentof mitochondrial oxidative phosphorylation.

AB - The ketogenic diet (KD), a high-fat, carbohydrate-restricted diet, is used as an alternative treatment for drug-resistant epileptic patients. Evidence suggests that compromised glucose metabolism has a significant role in the anticonvulsant action of the KD; however, it is unclear what part of the glucose metabolism that is important. The present study investigates how selective alterations in glycolysis and oxidative phosphorylation influence epileptiform activity induced by blocking K + currents and GABAA and NMDA receptors in the hippocampal slice preparation. Blocking glycolysis with the glucose derivative 2-deoxy-D-glucose (2-DG; 10 mM) gave a fast reduction of the frequency of interictal discharge (IED) consistent with findings in other in vitro models. However, this was followed by the induction of seizure-like discharges in area CA1 and CA3. Substituting glucose with sucrose (glucopenia) had effects similar to those of 2-DG, whereas substitution with L-lactate or pyruvate reduced the IED but had a less proconvulsant effect. Blockade of ATP-sensitive K + channels, glycine or adenosine 1 receptors, or depletion of the endogenous anticonvulsant compound glutathione did not prevent the actions of 2-DG. Baclofen (2 μM) reproduced the effect of 2-DG on IED activity. The proconvulsant effect of 2-DG could be reproduced by blocking the oxidative phosphorylation with the complex I toxin rotenone (4 μM). The data suggest that inhibition of IED, induced by 2-DG and glucopenia, is a direct consequence of impairment of glycolysis, likely exerted via a decreased recurrent excitatory synaptic transmission in area CA3. The accompanying proconvulsant effect is caused by an excitatory mechanism, depending on impairment of oxidative phosphorylation. NEW & NOTEWORTHY This study reveals two opposing effects of 2-deoxy-D-glucose (2-DG) and glucopenia on in vitro epileptiformdischarge observed during combined blockade of K + currents andGABA A receptors. Interictal-like activity is inhibited by a mechanismthat selectively depends on impairment of glycolysis and that resultsfrom a decrease in the strength of excitatory recurrent synaptictransmission in area CA3. In contrast, 2-DG and glucopenia facilitateictal-like activity by an excitatory mechanism, depending on impairmentof mitochondrial oxidative phosphorylation.

KW - 2-deoxy-D-glucose

KW - Epileptiform activity

KW - Glycolysis

KW - In vitro

KW - Oxidative phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=85047864034&partnerID=8YFLogxK

U2 - 10.1152/jn.00732.2017

DO - 10.1152/jn.00732.2017

M3 - Journal article

C2 - 29412775

SN - 0022-3077

VL - 119

SP - 1912

EP - 1923

JO - Journal of Neurophysiology

JF - Journal of Neurophysiology

IS - 5

ER -