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A Novel and Selective p38 Mitogen-Activated Protein Kinase Inhibitor Attenuates LPS-Induced Neuroinflammation in BV2 Microglia and a Mouse Model

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Abstract

Neuroinflammation is an important pathological feature in neurodegenerative diseases. Accumulating evidence has suggested that neuroinflammation is mainly aggravated by activated microglia, which are macrophage like cells in the central nervous system. Therefore, the inhibition of microglial activation may be considered for treating neuroinflammatory diseases. p38 mitogen-activated protein kinase (MAPK) has been identified as a crucial enzyme with inflammatory roles in several immune cells, and its activation also relates to neuroinflammation. Considering the proinflammatory roles of p38 MAPK, its inhibitors can be potential therapeutic agents for neurodegenerative diseases relating to neuroinflammation initiated by microglia activation. This study was designed to evaluate whether NJK14047, a recently identified novel and selective p38 MAPK inhibitor, could modulate microglia-mediated neuroinflammation by utilizing lipopolysaccharide (LPS)-stimulated BV2 cells and an LPS-injected mice model. Our results showed that NJK14047 markedly reduced the production of nitric oxide and prostaglandin E2 by downregulating the expression of various proinflammatory mediators such as nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α and interleukin-1β in LPS-induced BV2 microglia. Moreover, NJK14047 significantly reduced microglial activation in the brains of LPS-injected mice. Overall, these results suggest that NJK14047 significantly reduces neuroinflammation in cellular/vivo model and would be a therapeutic candidate for various neuroinflammatory diseases.

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Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), which was funded by the Ministry of Science, ICT & Future Planning (NRF-2017R1A5A2014768 and NRF-2016R1A2B4015169).

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Author notes

  1. Min Sung Gee and Sang-Won Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, South Korea

    Min Sung Gee, Sang-Won Kim, Soo Jin Lee, Nam-Jung Kim & Jong Kil Lee

  2. Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, South Korea

    Namkwon Kim, Myung Sook Oh & Kyung-Soo Inn

  3. Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea

    Hee Kyung Jin

  4. Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea

    Jae-sung Bae

Authors
  1. Min Sung Gee
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  2. Sang-Won Kim
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  3. Namkwon Kim
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  4. Soo Jin Lee
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Contributions

MSG and SYK performed the experiments, analyzed the data, and prepared the manuscript. NK and SJL performed animal and HPLC experiment, respectively. MSO, HKJ, JSB, KSI, NJK and JKL interpreted the data and reviewed the paper. NJK and JKL designed the study and wrote the manuscript. All authors discussed results and commented on the manuscript.

Corresponding authors

Correspondence to Nam-Jung Kim or Jong Kil Lee.

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The authors declare no conflict of interest.

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Gee, M.S., Kim, SW., Kim, N. et al. A Novel and Selective p38 Mitogen-Activated Protein Kinase Inhibitor Attenuates LPS-Induced Neuroinflammation in BV2 Microglia and a Mouse Model. Neurochem Res 43, 2362–2371 (2018). https://doi.org/10.1007/s11064-018-2661-1

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  • DOI: https://doi.org/10.1007/s11064-018-2661-1

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