title: Effects of aripiprazole and clozapine on the treatment of glycolytic carbon in PC12 cells.
abstract: Aripiprazole is the only atypical antipsychotic drug known to cause the phosphorylation of AMP-activated protein kinase (AMPK) in PC12 cells. However, the molecular mechanisms underlying this phosphorylation in aripiprazole-treated PC12 cells have not yet been clarified. Here, using PC12 cells, we show that these cells incubated for 24 h with aripiprazole at 50 μM and 25 mM glucose underwent a decrease in their NAD⁺/NADH ratio. Aripiprazole suppressed cytochrome c oxidase (COX) activity but enhanced the activities of pyruvate dehydrogenase (PDH), citrate synthase and Complex I. The changes in enzyme activities coincided well with those in NADH, NAD⁺, and NAD⁺/NADH ratio. However, the bioenergetic peril judged by the lowered COX activity might not be accompanied by excessive occurrence of apoptotic cell death in aripiprazole-treated cells, because the mitochondrial membrane potential was not decreased, but rather increased. On the other hand, when PC12 cells were incubated for 24 h with clozapine at 50 μM and 25 mM glucose, the NAD⁺/NADH ratio did not change. Also, the COX activity was decreased; and the PDH activity was enhanced. These results suggest that aripiprazole-treated PC12 cells responded to the bioenergetic peril more effectively than the clozapine-treated ones to return the ATP biosynthesis back toward its ordinary level. This finding might be related to the fact that aripiprazole alone causes phosphorylation of AMPK in PC12 cells.
authors.affiliation: Department of Physiology, Fujita Health University School of Medicine, Toyoake 470-1192, Japan. aota@fujita-hu.ac.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Ota
authors.forename: Akira
authors.initials: A
authors.lastname: Nakashima
authors.forename: Yoko S
authors.initials: YS
authors.lastname: Kaneko
authors.forename: Keiji
authors.initials: K
authors.lastname: Mori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagasaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takayanagi
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Itoh
authors.forename: Kazunao
authors.initials: K
authors.lastname: Kondo
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Nagatsu
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ota
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000068180:Aripiprazole; D002244:Carbon / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D008058:Dihydrolipoamide Dehydrogenase / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000378:metabolism; D045604:Extracellular Fluid / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D007658:Ketone Oxidoreductases / Q000235:genetics / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009243:NAD / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells / Q000187:drug effects / Q000201:enzymology; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019289:Pyruvic Acid / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015363:Quinolones; D012333:RNA, Messenger; D009243:NAD; D019344:Lactic Acid; D000244:Adenosine Diphosphate; D002244:Carbon; D000068180:Aripiprazole; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D010088:Oxidoreductases; D007521:Isocitrate Dehydrogenase; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+); D008058:Dihydrolipoamide Dehydrogenase; D003576:Electron Transport Complex IV; D007041:Hypoxanthine Phosphoribosyltransferase; D017346:Protein Serine-Threonine Kinases; D005947:Glucose; D003024:Clozapine