title: Metyrapone effects on systemic and cerebral energy metabolism.
abstract: Metyrapone is a cytochrome P(450) inhibitor that protects against ischemia- and excitotoxicity-induced brain damages in rodents. This study examines whether metyrapone would act on energy metabolism in a manner congruent with its neuroprotective effect. In a first investigation, the rats instrumented with telemetric devices measuring abdominal temperature, received i.p. injection of either metyrapone or saline. One hour after injection, their blood and hippocampus were sampled. Hippocampus metabolite concentrations were measured using (1)H high-resolution magic angle spinning-magnetic resonance spectroscopy ((1)H HRMAS-MRS). The hippocampus levels in phosphorylated mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) were measured by Western Blot analysis and those of c-fos and HSP70-2 mRNA were quantified by RT-PCR. In a second investigation, the rats received the same treatment and were sacrificed 1h after. The functioning of mitochondria was immediately studied on their whole brain. Metyrapone provoked a slight hypothermia which was correlated to the increase in blood glucose concentration. Metyrapone also increased blood lactate concentrations without modifying hippocampus lactate content. In the hippocampus, metyrapone decreased γ-aminobutyric acid (GABA) and glutamate levels but increased glutamine and N-acetyl-aspartate contents (NAA). Phosphorylated mTOR and AMPK and the c-fos and HSP70-2 mRNA levels were similar between treatment groups. Metyrapone did not modify blood corticosterone levels. Mitochondrial oxygen consumption was similar in both groups whatever the substrate used. These metabolic modifications, which take place without modifying blood glucocorticoid levels, are consistent with the neuroprotective properties of metyrapone as demonstrated in animal models.
authors.affiliation: Institut de Recherches Biomédicales des Armées (IRBA-CRSSA), Département des Environnements Opérationnels, 24 avenue du Maquis du Grésivaudan, F-38702 La Tronche Cédex, France. jb.drouet@crssa.net
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Drouet
authors.forename: Florence
authors.initials: F
authors.lastname: Fauvelle
authors.forename: Cécile
authors.initials: C
authors.lastname: Batandier
authors.forename: André
authors.initials: A
authors.lastname: Peinnequin
authors.forename: Antonia
authors.initials: A
authors.lastname: Alonso
authors.forename: Nadine
authors.initials: N
authors.lastname: Fidier
authors.forename: Renaud
authors.initials: R
authors.lastname: Maury
authors.forename: Laurent
authors.initials: L
authors.lastname: Poulet
authors.forename: Alain
authors.initials: A
authors.lastname: Buguet
authors.forename: Raymond
authors.initials: R
authors.lastname: Cespuglio
authors.forename: Frédéric
authors.initials: F
authors.lastname: Canini
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008797:Metyrapone / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; C490435:Hspa2 protein, rat; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D010100:Oxygen; D008797:Metyrapone