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Opposite effects of milnacipran, a serotonin norepinephrine reuptake inhibitor, on the levels of nitric oxide and brain-derived neurotrophic factor in mouse brain cortex

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Abstract

There is a growing body of evidence demonstrating that changes in the brain levels of nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) are implicated in the pathogenesis of major depression. We report here the effects of subchronic treatment of mice with milnacipran, a serotonin norepinephrine reuptake inhibitor, on the levels of NO and BDNF in mice. In vivo administration of milnacipran (10 mg/kg) for 14 days caused a significant decrease in nitrate and nitrite concentrations in the cerebral cortex and hippocampus, but not in the midbrain. Milnacipran (10 mg/kg, 14 days) also decreased the activity of NO synthase in the cerebral cortex. On the other hand, milnacipran (10 mg/kg, 14 days) increased the levels of BDNF protein and mRNA in the cerebral cortex. These findings suggest that milnacipran has opposite effects on the levels of NO and BDNF in the brain cortex, namely, downregulation of NO and upregulation of BDNF.

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Acknowledgements

We would like to thank Drs. Sei Nakata and Tsuyoshi Morishita (Department of 2nd Medicine, School of Medicine, University of Occupational and Environmental Health) for their helpful advice on the assay of NOx and NOS activity. We gratefully thank Dr. Yuko Shinohara (Ube Industries, Ltd., Ube, Japan) for her help of isolation of the mice brain areas. This research was supported, in part, by a special grant from Asahi Kasei Corporation (Tokyo, Japan) to NY. We are grateful to Asahi Kasei Corporation (Tokyo, Japan) for the generous gift of milnacipran.

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Authors and Affiliations

  1. Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan

    Atsuko Ikenouchi-Sugita, Reiji Yoshimura & Jun Nakamura

  2. Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan

    Yumiko Toyohira, Susumu Ueno, Masato Tsutsui & Nobuyuki Yanagihara

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  1. Atsuko Ikenouchi-Sugita
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  2. Yumiko Toyohira
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Correspondence to Nobuyuki Yanagihara.

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Ikenouchi-Sugita, A., Toyohira, Y., Yoshimura, R. et al. Opposite effects of milnacipran, a serotonin norepinephrine reuptake inhibitor, on the levels of nitric oxide and brain-derived neurotrophic factor in mouse brain cortex. Naunyn-Schmied Arch Pharmacol 380, 479–486 (2009). https://doi.org/10.1007/s00210-009-0467-z

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