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Effects of aripiprazole and clozapine on the treatment of glycolytic carbon in PC12 cells

  • Basic Neurosciences, Genetics and Immunology - Original Article
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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.

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Abbreviations

AAPD:

Atypical antipsychotic drug

AMPK:

AMP-activated protein kinase

Complex I:

NADH: ubiquinone oxidoreductase (mitochondrial respiratory chain complex I)

COX:

Cytochrome c oxidase

CS:

Citrate synthase

Δψm :

Mitochondrial membrane potential

Dld:

Dihydrolipoamide dehydrogenase

DMEM:

Dulbecco’s modified Eagle’s medium

EPS:

Extrapyramidal side effect

FGPD:

First-generation antipsychotic drug

HPRT:

Hypoxanthine–guanine phosphoribosyltransferase

IDH:

Isocitrate dehydrogenase

MCAD:

Medium-chain acyl-CoA dehydrogenase

PDH:

Pyruvate dehydrogenase

PDK:

Pyruvate dehydrogenase kinase

PPARα:

Peroxisome proliferator-activated receptor α

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Acknowledgments

This work was supported by grants-in-aid from Fujita Health University to AO. Ziprasidone was supplied by Pfizer (New York, NY, USA).

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Authors and Affiliations

  1. Department of Physiology, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan

    Akira Ota, Akira Nakashima, Yoko S. Kaneko, Keiji Mori & Hiroshi Nagasaki

  2. Division of Endocrinology and Metabolism, Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan

    Takeshi Takayanagi & Mitsuyasu Itoh

  3. Department of Pharmacology, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan

    Kazunao Kondo & Toshiharu Nagatsu

  4. Department of Neuropsychiatry, Tosei General Hospital, Seto, 489-8642, Japan

    Miyuki Ota

  5. Department of Psychiatry, Nagoya City University Medical School, Nagoya, 467-8601, Japan

    Miyuki Ota

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  1. Akira Ota
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  2. Akira Nakashima
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  3. Yoko S. Kaneko
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Correspondence to Akira Ota.

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Ota, A., Nakashima, A., Kaneko, Y.S. et al. Effects of aripiprazole and clozapine on the treatment of glycolytic carbon in PC12 cells. J Neural Transm 119, 1327–1342 (2012). https://doi.org/10.1007/s00702-012-0782-2

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  • DOI: https://doi.org/10.1007/s00702-012-0782-2

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