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Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy
Neuronal excitation is regulated by energy metabolism, and drug-resistant epilepsy can be suppressed by special diets. Here, we report that seizures and epileptiform activity are reduced by inhibition of the metabolic pathway via lactate dehydrogenase (LDH), a component of the astrocyte-neuron lacta...
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| Published in: | Science (American Association for the Advancement of Science) 2015-03, Vol.347 (6228), p.1362-1367 |
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| Main Authors: | , , , , |
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| Language: | English |
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| container_end_page | 1367 |
| container_issue | 6228 |
| container_start_page | 1362 |
| container_title | Science (American Association for the Advancement of Science) |
| container_volume | 347 |
| creator | Sada, Nagisa Lee, Suni Katsu, Takashi Otsuki, Takemi Inoue, Tsuyoshi |
| description | Neuronal excitation is regulated by energy metabolism, and drug-resistant epilepsy can be suppressed by special diets. Here, we report that seizures and epileptiform activity are reduced by inhibition of the metabolic pathway via lactate dehydrogenase (LDH), a component of the astrocyte-neuron lactate shuttle. Inhibition of the enzyme LDH hyperpolarized neurons, which was reversed by the downstream metabolite pyruvate. LDH inhibition also suppressed seizures in vivo in a mouse model of epilepsy. We further found that stiripentol, a clinically used antiepileptic drug, is an LDH inhibitor. By modifying its chemical structure, we identified a previously unknown LDH inhibitor, which potently suppressed seizures in vivo. We conclude that LDH inhibitors are a promising new group of antiepileptic drugs. |
| doi_str_mv | 10.1126/SCIENCE.AAA1299 |
| format | article |
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By modifying its chemical structure, we identified a previously unknown LDH inhibitor, which potently suppressed seizures in vivo. We conclude that LDH inhibitors are a promising new group of antiepileptic drugs.</description><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/SCIENCE.AAA1299</identifier><identifier>PMID: 25792327</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Anticonvulsants - chemistry ; Anticonvulsants - pharmacology ; Anticonvulsants - therapeutic use ; Dioxolanes - chemistry ; Dioxolanes - pharmacology ; Dioxolanes - therapeutic use ; Disease Models, Animal ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; L-Lactate Dehydrogenase - antagonists & inhibitors ; Membrane Potentials - drug effects ; Mice ; Mice, Inbred ICR ; Neurons - enzymology ; Neurons - physiology ; Patch-Clamp Techniques ; Safrole - chemistry ; Safrole - pharmacology ; Safrole - therapeutic use ; Seizures - drug therapy ; Subthalamic Nucleus - enzymology</subject><ispartof>Science (American Association for the Advancement of Science), 2015-03, Vol.347 (6228), p.1362-1367</ispartof><rights>Copyright © 2015, American Association for the Advancement of Science.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1027-455e0768bdab91982357ef351161cdf8f06a8129a3f72d13e01830ca78f2b2563</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25792327$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sada, Nagisa</creatorcontrib><creatorcontrib>Lee, Suni</creatorcontrib><creatorcontrib>Katsu, Takashi</creatorcontrib><creatorcontrib>Otsuki, Takemi</creatorcontrib><creatorcontrib>Inoue, Tsuyoshi</creatorcontrib><title>Epilepsy treatment. 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Targeting LDH enzymes with a stiripentol analog to treat epilepsy</title><author>Sada, Nagisa ; Lee, Suni ; Katsu, Takashi ; Otsuki, Takemi ; Inoue, Tsuyoshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1027-455e0768bdab91982357ef351161cdf8f06a8129a3f72d13e01830ca78f2b2563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Anticonvulsants - chemistry</topic><topic>Anticonvulsants - pharmacology</topic><topic>Anticonvulsants - therapeutic use</topic><topic>Dioxolanes - chemistry</topic><topic>Dioxolanes - pharmacology</topic><topic>Dioxolanes - therapeutic use</topic><topic>Disease Models, Animal</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>L-Lactate Dehydrogenase - antagonists & inhibitors</topic><topic>Membrane Potentials - drug effects</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>Neurons - enzymology</topic><topic>Neurons - physiology</topic><topic>Patch-Clamp Techniques</topic><topic>Safrole - chemistry</topic><topic>Safrole - pharmacology</topic><topic>Safrole - therapeutic use</topic><topic>Seizures - drug therapy</topic><topic>Subthalamic Nucleus - enzymology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sada, Nagisa</creatorcontrib><creatorcontrib>Lee, Suni</creatorcontrib><creatorcontrib>Katsu, Takashi</creatorcontrib><creatorcontrib>Otsuki, Takemi</creatorcontrib><creatorcontrib>Inoue, Tsuyoshi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sada, Nagisa</au><au>Lee, Suni</au><au>Katsu, Takashi</au><au>Otsuki, Takemi</au><au>Inoue, Tsuyoshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2015-03-20</date><risdate>2015</risdate><volume>347</volume><issue>6228</issue><spage>1362</spage><epage>1367</epage><pages>1362-1367</pages><eissn>1095-9203</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Neuronal excitation is regulated by energy metabolism, and drug-resistant epilepsy can be suppressed by special diets. Here, we report that seizures and epileptiform activity are reduced by inhibition of the metabolic pathway via lactate dehydrogenase (LDH), a component of the astrocyte-neuron lactate shuttle. Inhibition of the enzyme LDH hyperpolarized neurons, which was reversed by the downstream metabolite pyruvate. LDH inhibition also suppressed seizures in vivo in a mouse model of epilepsy. We further found that stiripentol, a clinically used antiepileptic drug, is an LDH inhibitor. By modifying its chemical structure, we identified a previously unknown LDH inhibitor, which potently suppressed seizures in vivo. We conclude that LDH inhibitors are a promising new group of antiepileptic drugs.</abstract><cop>United States</cop><pmid>25792327</pmid><doi>10.1126/SCIENCE.AAA1299</doi><tpages>6</tpages></addata></record> |
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| ispartof | Science (American Association for the Advancement of Science), 2015-03, Vol.347 (6228), p.1362-1367 |
| issn | 1095-9203 |
| language | eng |
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| source | Science Online_科学在线; JSTOR |
| subjects | Animals Anticonvulsants - chemistry Anticonvulsants - pharmacology Anticonvulsants - therapeutic use Dioxolanes - chemistry Dioxolanes - pharmacology Dioxolanes - therapeutic use Disease Models, Animal Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use L-Lactate Dehydrogenase - antagonists & inhibitors Membrane Potentials - drug effects Mice Mice, Inbred ICR Neurons - enzymology Neurons - physiology Patch-Clamp Techniques Safrole - chemistry Safrole - pharmacology Safrole - therapeutic use Seizures - drug therapy Subthalamic Nucleus - enzymology |
| title | Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy |
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