title: 2-Deoxy-d-glucose enhances tonic inhibition through the neurosteroid-mediated activation of extrasynaptic GABAAreceptors.
abstract: The inhibition of glycolysis exerts potent antiseizure effects, as demonstrated by the efficacy of ketogenic and low-glucose/nonketogenic diets in the treatment of drug-resistant epilepsy. ATP-sensitive potassium (KATP) channels have been initially identified as the main determinant of the reduction of neuronal hyperexcitability. However, a plethora of other mechanisms have been proposed. Herein, we report the ability of 2-deoxy-d-glucose (2-DG), a glucose analog that inhibits glycolytic enzymes, of potentiating γ-aminobutyric acid (GABA)ergic tonic inhibition via neurosteroid-mediated activation of extrasynaptic GABAAreceptors.
  
  
  
  Acute effects of 2-DG on the ATP-sensitive potassium currents, GABAergic tonic inhibition, firing activity, and interictal events were assessed in hippocampal slices by whole-cell patch-clamp and local field potential recordings of dentate gyrus granule cells.
  
  
  
  Acute application of 2-DG activates two distinct outward conductances: a KATPchannel-mediated current and a bicuculline-sensitive tonic current. The effect of 2-DG on such GABAergic tonic currents was fully prevented by either finasteride or PK11195, which are specific inhibitors of the neurosteroidogenesis pathway acting via different mechanisms. Moreover, the oxidized form of vitamin C, dehydroascorbic acid, known for its ability to induce neurosteroidogenesis, also activated a bicuculline-sensitive tonic current in a manner indistinguishable from that of 2-DG. Finally, we found that the enhancement of KATPcurrent by 2-DG primarily regulates intrinsic firing rate of granule cells, whereas the increase of the GABAergic tonic current plays a key role in reducing the frequency of interictal events evoked by treatment of hippocampal slices with the convulsive agent 4-aminopyridine.
  
  
  
  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.
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy.|Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Forte
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Lucian
authors.initials: L
authors.lastname: Medrihan
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Cappetti
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy.|Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Baldelli
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy.|Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007461:Iodoacetates / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D018079:Receptors, GABA / Q000378:metabolism*; D018709:Statistics, Nonparametric; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D000970:Antineoplastic Agents; C463819:Bzrp protein, mouse; D004791:Enzyme Inhibitors; D058787:GABA-A Receptor Antagonists; D007004:Hypoglycemic Agents; D007461:Iodoacetates; D007546:Isoquinolines; D026902:Potassium Channel Blockers; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; D018120:Finasteride; D003847:Deoxyglucose; D015761:4-Aminopyridine; D005905:Glyburide; D001640:Bicuculline; C037850:PK 11195
keywords: 2-Deoxy-d-glucose; Ascorbic acid; GABA tonic inhibition; Glycolysis; Neurosteroid metabolism; Pentose phosphate pathway