title: The ketogenic diet metabolite beta-hydroxybutyrate (β-HB) reduces incidence of seizure-like activity (SLA) in a Katp- and GABAb-dependent manner in a whole-animal Drosophila melanogaster model.
abstract: The high-fat, low-carbohydrate ketogenic diet (KD) is an effective clinical treatment for epilepsy in juveniles, especially for drug-resistant seizures. The KD results in elevated production of ketone bodies (KB's), such as beta-hydroxybutyrate (β-HB), which are thought to have anticonvulsant properties; however, their exact mechanism of action is unknown. In vitro, KB effects on reducing neuronal firing rates are mediated in part by Katpchannel activity and GABAbsignaling. In order to study metabolic and pharmacological effects in a whole-animal model, we used the eas "bang-sensitive" (BS) mutant strain of Drosophila, which exhibits seizure-like activity (SLA) upon mechanical stimulation. Direct application of the KB β-HB to food reduced BS SLA. Application either of tolbutamide, a Katpblocker, or of CGP-55845, a GABAbantagonist, concomitantly with β-HB, partially reversed these KB effects on SLA, verifying a role for Katpchannels and GABAbsignaling in mediating the anticonvulsant effects of KB's and validating this whole-animal model of KD effects on seizure.
authors.affiliation: Department of Biological Sciences, Mount Holyoke College, South Hadley, MA 01075, United States; Program in Neuroscience and Behavior, Mount Holyoke College, South Hadley, MA 01075, United States.
authors.forename: Jinglu
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, Mount Holyoke College, South Hadley, MA 01075, United States; Program in Biochemistry, Mount Holyoke College, South Hadley, MA 01075, United States.
authors.forename: Emma I
authors.initials: EI
authors.lastname: O'Leary
authors.affiliation: Department of Biological Sciences, Mount Holyoke College, South Hadley, MA 01075, United States; Program in Neuroscience and Behavior, Mount Holyoke College, South Hadley, MA 01075, United States; Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, United States; Connecticut Institute for the Brain and Cognitive Sciences, United States. Electronic address: geoffrey.tanner@uconn.edu.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Tanner
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000627:therapeutic use*; D000818:Animals; D030801:Animals, Genetically Modified; D000927:Anticonvulsants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster; D018756:GABA Antagonists / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D018709:Statistics, Nonparametric; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D029721:Drosophila Proteins; D018756:GABA Antagonists; D007004:Hypoglycemic Agents; D054086:KATP Channels; D010721:Phosphinic Acids; D011412:Propanolamines; D018080:Receptors, GABA-B; C085075:CGP 55845A; D014044:Tolbutamide; D020155:3-Hydroxybutyric Acid
keywords: Bang sensitive; GABA(b) receptor; K(atp) channel; Ketogenic diet; Ketone bodies; Seizure model