Aripiprazole increases NADPH level in PC12 cells: The role of NADPH oxidase

Hiroshi Nagasaki, Akira Nakashima, Yoko S. Kaneko, Yu Kodani, Takeshi Takayanagi, Mitsuyasu Itoh, Kazunao Kondo, Toshiharu Nagatsu, Yoji Hamada, Miyuki Ota, Akira Ota

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3 Citations (Scopus)

Abstract

In aripiprazole-treated PC12 cells, we previously showed that the mitochondrial membrane potential (Δψm) was rather increased in spite of lowered cytochrome c oxidase activity. To address these inconsistent results, we focused the NADPH generation by glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway (PPP), to titrate reactive oxygen species (ROS) that results in the Δψm maintenance. G6PD may be also involved in another inconsistent result of lowered intracellular lactate level in aripiprazole-treated PC12 cells, because PPP competes glucose-6-phosphate with the glycolytic pathway, resulting in the downregulation of glycolysis. Therefore, we assayed intracellular amounts of NADPH, ROS, and the activities of the enzymes generating or consuming NADPH (G6PD, NADP+-dependent isocitrate dehydrogenase, NADP+-dependent malic enzyme, glutathione reductase, and NADPH oxidase [NOX]) and estimated glycolysis in 50 μM aripiprazole-, clozapine-, and haloperidol-treated PC12 cells. NADPH levels were enhanced only in aripiprazole-treated ones. Only haloperidol increased ROS. However, the enzyme activities did not show significant changes toward enhancing NADPH level except for the aripiprazole-induced decrease in NOX activity. Thus, the lowered NOX activity could have contributed to the aripiprazole-induced increase in the NADPH level by lowering ROS generation, resulting in maintained Δψm. Although the aforementioned assumption was invalid, the ratio of fructose-1,6-bisphosphate to fructose-6-phosphate was decreased by all antipsychotics examined. Pyruvate kinase activity was enhanced only by aripiprazole. In summary, these observations indicate that aripiprazole possibly possesses the pharmacological superiority to clozapine and haloperidol in the ROS generation and the adjustment of glycolytic pathway.

Original languageEnglish
Pages (from-to)91-103
Number of pages13
JournalJournal of Neural Transmission
Volume121
Issue number1
DOIs
Publication statusPublished - 01-01-2014

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry

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    Nagasaki, H., Nakashima, A., Kaneko, Y. S., Kodani, Y., Takayanagi, T., Itoh, M., Kondo, K., Nagatsu, T., Hamada, Y., Ota, M., & Ota, A. (2014). Aripiprazole increases NADPH level in PC12 cells: The role of NADPH oxidase. Journal of Neural Transmission, 121(1), 91-103. https://doi.org/10.1007/s00702-013-1075-0