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Anti-depressant effects of phosphodiesterase 3 inhibitor cilostazol in chronic mild stress-treated mice after ischemic stroke

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Abstract

Rationale

Phosphodiesterase 3 (PDE3) inhibitor cilostazol ameliorates negative effects of cerebral hypoperfusion against cerebral ischemic injury through the phosphodiesterase 3-cyclic adenosine monophosphate (cAMP) signaling cascade.

Objectives

We investigated the question of whether cilostazol would have an anti-depressant effect on chronic mild stress (CMS)-treated mice after ischemic stroke.

Methods

An animal model of post-stroke depression was developed by additional CMS procedures in middle cerebral artery occlusion (MCAO). We performed behavioral, histological, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunohistochemical, Western blot and enzyme linked immunosorbent assays (ELISA).

Results

In the open field, sucrose preference, forced swim and Morris water maze test, treatment with cilostazol resulted in reduction of all depressive behaviors examined, particularly in the Morris water maze test. Treatment with cilostazol reduced prominent atrophic changes in the ipsilateral striatum and hippocampus of CMS-treated ischemic mice through inhibition of neuronal cell death and microglial activation. In addition, treatment of the CMS-treated ischemic mice with cilostazol resulted in significantly increased phosphorylation of cAMP response element-binding protein (CREB) and expression of mature brain-derived neurotrophic factor (BDNF) with its receptor tropomyosin receptor kinase B (TrkB) in the ipsilateral striatum and hippocampus. Phosphorylation of CREB was also demonstrated in the dopaminergic neurons of the midbrain. Treatment with cilostazol also resulted in an increased number of newly formed cells and enhanced differentiation into neurons in the ipsilateral striatum and hippocampus.

Conclusions

Our results suggest that phosphodiesterase 3 inhibitor cilostazol may have anti-depressant effects on post-stroke depression through inhibition of neurodegeneration in the primary lesion and secondary extrafocal sites and promotion of neurogenesis. These beneficial effects on post-stroke depression may be involved in activation of CREB/BDNF signaling.

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (2014R1A5A2009936).

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Authors and Affiliations

  1. Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea

    Yu Ri Kim, Ha Neui Kim, Hwa Kyoung Shin & Byung Tae Choi

  2. Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, 626-870, Republic of Korea

    Ha Neui Kim, Hwa Kyoung Shin & Byung Tae Choi

  3. Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, 626-870, Republic of Korea

    Ki Whan Hong

  4. Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Gyeongnam, Yangsan, 626-870, Republic of Korea

    Hwa Kyoung Shin & Byung Tae Choi

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  1. Yu Ri Kim
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  2. Ha Neui Kim
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Corresponding author

Correspondence to Byung Tae Choi.

Ethics declarations

All experiments were approved by the Pusan National University Animal Care and Use Committee in accordance with the National Institutes of Health Guidelines (approval number, PNU-2015-0850).

Conflict of interest

The authors declare that they have no competing interests.

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Kim, Y.R., Kim, H.N., Hong, K.W. et al. Anti-depressant effects of phosphodiesterase 3 inhibitor cilostazol in chronic mild stress-treated mice after ischemic stroke. Psychopharmacology 233, 1055–1066 (2016). https://doi.org/10.1007/s00213-015-4185-6

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  • DOI: https://doi.org/10.1007/s00213-015-4185-6

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