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Treatment with Histone Deacetylase Inhibitor Attenuates Peripheral Inflammation-Induced Cognitive Dysfunction and Microglial Activation: The Effect of SAHA as a Peripheral HDAC Inhibitor

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Abstract

It has been demonstrated that peripheral inflammation induces cognitive dysfunction. Several histone deacetylase (HDAC) inhibitors ameliorate cognitive dysfunction in animal models of not only peripheral inflammation but also Alzheimer’s disease. However, it is not clear which HDAC expressed in the central nervous system or peripheral tissues is involved in the therapeutic effect of HDAC inhibition on cognitive dysfunction. Hence, the present study investigated the effect of peripheral HDAC inhibition on peripheral inflammation-induced cognitive dysfunction. Suberoylanilide hydroxamic acid (SAHA), a pan-HDAC inhibitor that is mainly distributed in peripheral tissues after intraperitoneal administration, was found to prevent peripheral inflammation-induced cognitive dysfunction. Moreover, pretreatment with SAHA dramatically increased mRNA expression of interleukin-10, an anti-inflammatory cytokine, in peripheral and central tissues and attenuated peripheral inflammation-induced microglial activation in the CA3 region of the hippocampus. Minocycline, a macrophage/microglia inhibitor, also ameliorated cognitive dysfunction. Furthermore, as a result of treatment with liposomal clodronate, depletion of peripheral macrophages partially ameliorated the peripheral inflammation-evoked cognitive dysfunction. Taken together, these findings demonstrate that inhibition of peripheral HDAC plays a critical role in preventing cognitive dysfunction induced by peripheral inflammation via the regulation of anti-inflammatory cytokine production and the inhibition of microglial functions in the hippocampus. Thus, these findings could provide support for inhibition of peripheral HDAC as a novel therapeutic strategy for inflammation-induced cognitive dysfunction.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported in part by grants from the Smoking Research Foundation. Experiments were carried out using equipment at the Analysis Center of Life Science, Hiroshima University and the Research Center for Molecular Medicine, Faculty of Medicine, Hiroshima University (Grant number: JPMXS0410300320). We thank Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.

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  1. Naoki Takaoka & Seigo Sanoh

    Present address: School of Pharmaceutical Sciences, Wakayama Medical University, 25-1 Shichibancho, Wakayama, 640-8156, Japan

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  1. Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8553, Japan

    Naoki Takada, Yoki Nakamura, Keisuke Ikeda, Kazue Hisaoka-Nakashima, Yoshihiro Nakata & Norimitsu Morioka

  2. Department of Neurochemistry and Environmental Health Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8553, Japan

    Naoki Takaoka, Seigo Sanoh & Yaichiro Kotake

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Takada, N., Nakamura, Y., Ikeda, K. et al. Treatment with Histone Deacetylase Inhibitor Attenuates Peripheral Inflammation-Induced Cognitive Dysfunction and Microglial Activation: The Effect of SAHA as a Peripheral HDAC Inhibitor. Neurochem Res 46, 2285–2296 (2021). https://doi.org/10.1007/s11064-021-03367-1

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