{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T09:04:34Z","timestamp":1782551074874,"version":"3.54.5"},"reference-count":75,"publisher":"American Physiological Society","issue":"5","funder":[{"DOI":"10.13039\/501100006309","name":"RiisFort Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006309","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100012526","name":"Faculty of Health Sciences, Aarhus University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012526","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurophysiology"],"published-print":{"date-parts":[[2018,5,1]]},"abstract":"<jats:p>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<jats:sup>+<\/jats:sup>currents and GABA<jats:sub>A<\/jats:sub>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<jats:sup>+<\/jats:sup>channels, glycine or adenosine 1 receptors, or depletion of the endogenous anticonvulsant compound glutathione did not prevent the actions of 2-DG. Baclofen (2 \u03bcM) 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 \u03bcM). 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.<\/jats:p><jats:p>NEW &amp; NOTEWORTHY This study reveals two opposing effects of 2-deoxy-d-glucose (2-DG) and glucopenia on in vitro epileptiform discharge observed during combined blockade of K<jats:sup>+<\/jats:sup>currents and GABA<jats:sub>A<\/jats:sub>receptors. Interictal-like activity is inhibited by a mechanism that selectively depends on impairment of glycolysis and that results from a decrease in the strength of excitatory recurrent synaptic transmission in area CA3. In contrast, 2-DG and glucopenia facilitate ictal-like activity by an excitatory mechanism, depending on impairment of mitochondrial oxidative phosphorylation.<\/jats:p>","DOI":"10.1152\/jn.00732.2017","type":"journal-article","created":{"date-parts":[[2018,2,7]],"date-time":"2018-02-07T18:47:38Z","timestamp":1518029258000},"page":"1912-1923","source":"Crossref","is-referenced-by-count":16,"title":["Opposing effects of 2-deoxy-<scp>d<\/scp>-glucose on interictal- and ictal-like activity when K<sup>+<\/sup>currents and GABA<sub>A<\/sub>receptors are blocked in rat hippocampus in vitro"],"prefix":"10.1152","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1666-4488","authenticated-orcid":false,"given":"Steen","family":"Nedergaard","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3402-4126","authenticated-orcid":false,"given":"Mogens","family":"Andreasen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(99)02269-6"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-3806(97)00222-8"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.20335"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.08R01CR"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2005.09.006"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(19980301)51:5<636::AID-JNR11>3.0.CO;2-0"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-1211(98)00059-X"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1996.75.5.2017"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1126\/science.1076510"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1994.71.4.1574"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(92)90167-Z"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2013.00134"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2147\/NDT.S84852"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.20.1.22"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(00)00026-5"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-007-7332-3"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1042\/AN20120021"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-21-07873.2003"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.06.005"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13578"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2014.170"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nn1791"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02593.x"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(94)90523-1"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s00249-002-0241-3"},{"key":"B26","doi-asserted-by":"crossref","first-page":"7558","DOI":"10.1016\/S0021-9258(18)35980-5","volume":"254","author":"Griffith OW","year":"1979","journal-title":"J Biol Chem"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.04.006"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/B978-012373961-2.00097-7"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-197605000-00006"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211617200"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2013.222"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1990.tb04588.x"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1995.75.4.689"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410240502"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2013.01.006"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00222.2006"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0055-10.2010"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nn1839"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2003.01603.x"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2006.04665.x"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1987.57.1.325"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.02.015"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2016.00082"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12041"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3163-07.2007"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1080\/09687680110047373"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00629.2016"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0132-07.2007"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.2000.7481"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2012.07670.x"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/0013-4694(73)90131-4"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(98)00224-8"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2013.01.010"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.18.8414"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.1992.5"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1991.tb09865.x"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.12.042"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-1211(01)00184-X"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2015.07.034"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00100.2017"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2013.11.005"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00656.2004"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.04883.x"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21603"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/651"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(87)90339-8"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2011.11.003"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1996.tb00042.x"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1677\/jme.0.0320129"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00244.2002"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1993.tb12884.x"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059829"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-012-0958-z"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2008.01843.x"},{"key":"B75","first-page":"368","volume":"75","author":"Zhao YT","year":"1997","journal-title":"Can J Physiol Pharmacol"}],"container-title":["Journal of Neurophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/jn.00732.2017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,14]],"date-time":"2022-08-14T01:27:46Z","timestamp":1660440466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/jn.00732.2017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,1]]},"references-count":75,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018,5,1]]}},"alternative-id":["10.1152\/jn.00732.2017"],"URL":"https:\/\/doi.org\/10.1152\/jn.00732.2017","relation":{},"ISSN":["0022-3077","1522-1598"],"issn-type":[{"value":"0022-3077","type":"print"},{"value":"1522-1598","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,1]]}}}