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The diet treatment markedly increases ketone bodies (acetoacetate and \u03b2\u2010hydroxybutyrate), which work as energy metabolites in the brain. Here, we investigated effects of acetoacetate on voltage\u2010dependent Ca\n                      <jats:sup>2+<\/jats:sup>\n                      channels (\n                      <jats:styled-content style=\"fixed-case\">VDCC<\/jats:styled-content>\n                      s) in pyramidal cells of the hippocampus. We further explored an acetoacetate analog that inhibited\n                      <jats:styled-content style=\"fixed-case\">VDCC<\/jats:styled-content>\n                      s in pyramidal cells, reduced excitatory postsynaptic currents (\n                      <jats:styled-content style=\"fixed-case\">EPSC<\/jats:styled-content>\n                      s), and suppressed seizures in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The effects of acetoacetate and its analogs on\n                      <jats:styled-content style=\"fixed-case\">VDCC<\/jats:styled-content>\n                      s and\n                      <jats:styled-content style=\"fixed-case\">EPSC<\/jats:styled-content>\n                      s were evaluated using patch\u2010clamp recordings from\n                      <jats:styled-content style=\"fixed-case\">CA<\/jats:styled-content>\n                      1 pyramidal cells of mouse hippocampal slices. The in vivo effects of these reagents were also evaluated using a chronic seizure model induced by intrahippocampal injection of kainate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Acetoacetate inhibited\n                      <jats:styled-content style=\"fixed-case\">VDCC<\/jats:styled-content>\n                      s in pyramidal cells of hippocampal slices, and reduced\n                      <jats:styled-content style=\"fixed-case\">EPSC<\/jats:styled-content>\n                      s in slices exhibiting epileptiform activity. More potent\n                      <jats:styled-content style=\"fixed-case\">EPSC<\/jats:styled-content>\n                      inhibitors were then explored by modifying the chemical structure of acetoacetate, and 2\u2010phenylbutyrate was identified as an acetoacetate analog that inhibited\n                      <jats:styled-content style=\"fixed-case\">VDCC<\/jats:styled-content>\n                      s and\n                      <jats:styled-content style=\"fixed-case\">EPSC<\/jats:styled-content>\n                      s more potently. Although acetoacetate is known to inhibit vesicular glutamate transporters (\n                      <jats:styled-content style=\"fixed-case\">VGLUT<\/jats:styled-content>\n                      s), 2\u2010phenylbutyrate did not inhibit\n                      <jats:styled-content style=\"fixed-case\">VGLUT<\/jats:styled-content>\n                      s, showing that 2\u2010phenylbutyrate is an acetoacetate analog that preferably inhibits\n                      <jats:styled-content style=\"fixed-case\">VDCC<\/jats:styled-content>\n                      s. In addition, 2\u2010phenylbutyrate markedly reduced\n                      <jats:styled-content style=\"fixed-case\">EPSC<\/jats:styled-content>\n                      s in slices exhibiting epileptiform activity, and suppressed hippocampal seizures in vivo in a mouse model of epilepsy. The in vivo antiseizure effects of 2\u2010phenylbutyrate were more potent than those of acetoacetate. Finally, intraperitoneal 2\u2010phenylbutyrate was delivered to the brain, and its brain concentration reached the level enough to reduce\n                      <jats:styled-content style=\"fixed-case\">EPSC<\/jats:styled-content>\n                      s.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      These results demonstrate that 2\u2010phenylbutyrate is an acetoacetate analog that inhibits\n                      <jats:styled-content style=\"fixed-case\">VDCC<\/jats:styled-content>\n                      s and\n                      <jats:styled-content style=\"fixed-case\">EPSC<\/jats:styled-content>\n                      s in pyramidal cells, suppresses hippocampal seizures in vivo, and has brain penetration ability. Thus 2\u2010phenylbutyrate provides a useful chemical structure as a lead compound to develop new antiseizure drugs originating from ketone bodies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.13718","type":"journal-article","created":{"date-parts":[[2017,3,11]],"date-time":"2017-03-11T03:59:54Z","timestamp":1489204794000},"page":"845-857","source":"Crossref","is-referenced-by-count":34,"title":["Neuronal inhibition and seizure suppression by acetoacetate and its analog, 2\u2010phenylbutyrate"],"prefix":"10.1111","volume":"58","author":[{"given":"Atsushi","family":"Kadowaki","sequence":"first","affiliation":[{"name":"Department of Biophysical Chemistry Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagisa","family":"Sada","sequence":"additional","affiliation":[{"name":"Department of Biophysical Chemistry Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narinobu","family":"Juge","sequence":"additional","affiliation":[{"name":"Advanced Science Research Center Okayama University Okayama Japan"},{"name":"Precursory Research for Embryonic Science and Technology Japan Science and Technology Agency Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayaka","family":"Wakasa","sequence":"additional","affiliation":[{"name":"Department of Biophysical Chemistry Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Moriyama","sequence":"additional","affiliation":[{"name":"Advanced Science Research Center Okayama University Okayama Japan"},{"name":"Department of Membrane Biochemistry Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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