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Influence of Tacrolimus on Depressive-Like Behavior in Diabetic Rats Through Brain-Derived Neurotrophic Factor Regulation in the Hippocampus

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Abstract

The neurotoxicity of immunosuppressive agents and diabetes mellitus are known risk factors of neurological complications in kidney transplant recipients. The aim of the present study was to investigate the influence of tacrolimus on brain-derived neurotrophic factor (BDNF), the critical protein for maintenance of neuronal functions, in the hippocampus in a diabetic condition. A diabetic rat model was established by a single streptozotocin injection (60 mg/kg). Control and diabetic rats then received daily tacrolimus (1.5 mg/kg per day) injections for 6 weeks. BDNF expression in the hippocampus was examined in the dentate gyrus (DG) and CA3 region using immunohistochemistry. There was a significant decrease of BDNF expression in the DG and CA3 region in tacrolimus-treated and diabetic rats compared with that of the control group injected with vehicle only. However, there was no difference in BDNF expression between the two experimental groups. Tacrolimus treatment in diabetic rats further decreased the BDNF expression level in the DG and CA3 region. Interestingly, mossy fiber sprouting, demonstrated by prominent punctate immunolabeling of BDNF with synaptoporin, was observed in the diabetic group treated with tacrolimus, which localized at the stratum oriens of the CA3 region. These data suggest that tacrolimus treatment or a diabetic condition decreases BDNF expression in the hippocampus, and that tacrolimus treatment in the diabetic condition further injures the CA3 region of the hippocampus. In addition to BDNF expression, decreased locomotor activity and evident depressive behavior were observed in tacrolimus-treated diabetic rats. Moreover, there were significant decreases of the mRNA levels of γ-aminobutyric acid and serotonin receptors in the diabetic hippocampus with tacrolimus treatment. This finding suggests that tacrolimus treatment may cause further psychiatric and neurological complications for patients with diabetes, and should thus be used with caution.

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Funding

This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C3417) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B07044219).

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Authors and Affiliations

  1. Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, The Catholic University of Korea, School of Medicine, 222 Banpo-daero, Seocho-gu, Seoul, 06501, Republic of Korea

    Yoo Jin Shin, Sun Woo Lim, Kang Luo, Yi Quan, Sheng Cui, Eun Jeong Ko, Byung Ha Chung & Chul Woo Yang

  2. Transplant Research Center, The Catholic University of Korea, School of Medicine, 222 Banpo-daero, Seocho-gu, Seoul, 06501, Republic of Korea

    Yoo Jin Shin, Sun Woo Lim, Kang Luo, Yi Quan, Sheng Cui, Eun Jeong Ko, Byung Ha Chung & Chul Woo Yang

  3. Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam, 13135, Republic of Korea

    Yeon Tae Chun, Jiyeong Lee & Hee Gyoo Kang

  4. Integrative Research Support Center, The Catholic University of Korea, School of Medicine, 222 Banpo-daero, Seocho-gu, Seoul, 06501, Republic of Korea

    Yeon Tae Chun

  5. Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, School of Medicine, 222 Banpo-daero, Seocho-gu, Seoul, 06501, Republic of Korea

    Eun Jeong Ko, Byung Ha Chung & Chul Woo Yang

  6. Department of Clinical Laboratory Science, Dongnam Health University, 50 Cheonchon-ro 74-Gil, Jangan-gu, Suwon-si, Gyeonggi-do, 16328, Republic of Korea

    Seongno Hong

  7. Department of Anatomy, Catholic Neuroscience Institute, Cell Death Disease Research Center, The Catholic University of Korea, School of Medicine, 222 Banpo-daero, Seocho-gu, Seoul, 06501, Republic of Korea

    Mun Yong Lee

  8. Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Seongnam, 13135, Republic of Korea

    Hee Gyoo Kang

Authors
  1. Yoo Jin Shin
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  2. Yeon Tae Chun
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  3. Sun Woo Lim
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  4. Kang Luo
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  5. Yi Quan
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  6. Sheng Cui
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  7. Eun Jeong Ko
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  8. Byung Ha Chung
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  9. Jiyeong Lee
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  10. Seongno Hong
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  11. Mun Yong Lee
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  12. Hee Gyoo Kang
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  13. Chul Woo Yang
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Contributions

Y-J Shin, Y-T Chun, S-W Lim, and C-W Yang: designed the research and wrote the report; K Luo, Y Quan, and C Sheng: conducted the animal experiments; E-J Ko, J Lee, and S Hong: performed the histological experiments; Y-J Shin, Y-T Chun, B-H Chung, M-Y Lee, H-G Kang, and C-W Yang.: analyzed the data and edited the manuscript.

Corresponding authors

Correspondence to Hee Gyoo Kang or Chul Woo Yang.

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Y-J Shin and Y-T Chun are co-first authors.

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Shin, Y.J., Chun, Y.T., Lim, S.W. et al. Influence of Tacrolimus on Depressive-Like Behavior in Diabetic Rats Through Brain-Derived Neurotrophic Factor Regulation in the Hippocampus. Neurotox Res 36, 396–410 (2019). https://doi.org/10.1007/s12640-019-00062-6

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  • DOI: https://doi.org/10.1007/s12640-019-00062-6

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