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Cilostazol improves hippocampus-dependent long-term memory in mice

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Abstract

Rationale

Phosphodiesterases (PDEs) play an important role in the regulation of intracellular signaling mediated by cyclic adenosine monophosphate (cAMP). Recently, several PDE inhibitors were assessed for their possible cognitive enhancing properties. However, little is known about the effect of PDE3 inhibitors on memory function.

Objectives

We examined how the PDE3 inhibitor cilostazol affects C57BL/6 J mice as they perform various behavioral tasks. After behavioral assessment, brains of the mice were analyzed immunohistochemically to quantify the phosphorylation of cAMP-responsive element binding protein (CREB), a downstream component of the cAMP pathway.

Results

Oral administration of cilostazol significantly enhanced recollection of the exact platform location in the Morris water maze probe test. Cilostazol also improved context-dependent long-term fear memory, without affecting short-term memory. No apparent effect was observed in cue-dependent fear memory. The results suggest that cilostazol selectively improves hippocampus-dependent long-term memory in these tasks. Cilostazol also significantly increased the number of phosphorylated-CREB-positive cells in hippocampal dentate gyrus.

Conclusions

These results suggest that cilostazol may exert its beneficial effects on learning and memory by enhancing the cAMP system in hippocampus, where it increases intracellular cAMP activity.

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Acknowledgments

Authors thank Ms. Masako Suzuki, Tomoko Arasaki, and Kazuko Nakanishi for their technical help. This work is supported in part by JSPS KAKENHI (24730642, 25293331, and 25560382), the Naito Foundation, Japan Foundation for Aging and Health, and Otsuka Pharmaceutical Co., Ltd.

Conflict of interest

Authors declare that there are no competing interests.

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Authors and Affiliations

  1. Aging Neuroscience Research Team, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0015, Japan

    Shuichi Yanai, Yuki Semba & Shogo Endo

  2. First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, 771-0192, Japan

    Hideki Ito

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  1. Shuichi Yanai
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  2. Yuki Semba
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  4. Shogo Endo
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Correspondence to Shogo Endo.

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Yanai, S., Semba, Y., Ito, H. et al. Cilostazol improves hippocampus-dependent long-term memory in mice. Psychopharmacology 231, 2681–2693 (2014). https://doi.org/10.1007/s00213-014-3442-4

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