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Open AccessArticle

HDAC8 Inhibitor WK2-16 Therapeutically Targets Lipopolysaccharide-Induced Mouse Model of Neuroinflammation and Microglial Activation

1
School of Pharmaceutical Sciences, National Yang-Ming University, Taipei 112-21, Taiwan
2
Graduate Institute of Medical Sciences and Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110-31, Taiwan
3
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110-31, Taiwan
4
Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 110-31, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(2), 410; https://doi.org/10.3390/ijms20020410
Received: 12 December 2018 / Revised: 14 January 2019 / Accepted: 15 January 2019 / Published: 18 January 2019
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
Glial activation and neuroinflammatory processes play important roles in the pathogenesis of brain abscess and neurodegenerative diseases. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which contribute to the exacerbation of neuronal cell death. The inhibition of glial activation has been shown to alleviate neurodegenerative conditions. The present study was to investigate the specific HDAC8 inhibitor WK2-16, especially its effects on the neuroinflammatory responses through glial inactivation. WK2-16 significantly reduced the gelatinolytic activity of MMP-9, and expression of COX-2/iNOS proteins in striatal lipopolysaccharide (LPS)-induced neuroinflammation in C57BL/6 mice. The treatment of WK2-16 markedly improved neurobehavioral deficits. Immunofluorescent staining revealed that WK2-16 reduced LPS-stimulated astrogliosis and microglial activation in situ. Consistently, cellular studies revealed that WK2-16 significantly suppressed LPS-induced mouse microglia BV-2 cell proliferation. WK2-16 was proven to concentration-dependently induce the levels of acetylated SMC3 in microglial BV-2 cells. It also reduced the expression of COX-2/iNOS proteins and TNF-α production in LPS-activated microglial BV-2 cells. The signaling studies demonstrated that WK2-16 markedly inhibited LPS-activated STAT-1/-3 and Akt activation, but not NF-κB or MAPK signaling. In summary, the HDAC8 inhibitor WK2-16 exhibited neuroprotective effects through its anti-neuroinflammation and glial inactivation properties, especially in microglia in vitro and in vivo. View Full-Text
Keywords: HDAC8 inhibitor; WK2-16; neuroinflammation; microglia; STAT; Akt HDAC8 inhibitor; WK2-16; neuroinflammation; microglia; STAT; Akt
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MDPI and ACS Style

Lin, F.-L.; Yen, J.-L.; Kuo, Y.-C.; Kang, J.-J.; Cheng, Y.-W.; Huang, W.-J.; Hsiao, G. HDAC8 Inhibitor WK2-16 Therapeutically Targets Lipopolysaccharide-Induced Mouse Model of Neuroinflammation and Microglial Activation. Int. J. Mol. Sci. 2019, 20, 410. https://doi.org/10.3390/ijms20020410

AMA Style

Lin F-L, Yen J-L, Kuo Y-C, Kang J-J, Cheng Y-W, Huang W-J, Hsiao G. HDAC8 Inhibitor WK2-16 Therapeutically Targets Lipopolysaccharide-Induced Mouse Model of Neuroinflammation and Microglial Activation. International Journal of Molecular Sciences. 2019; 20(2):410. https://doi.org/10.3390/ijms20020410

Chicago/Turabian Style

Lin, Fan-Li; Yen, Jing-Lun; Kuo, Yu-Cheng; Kang, Jaw-Jou; Cheng, Yu-Wen; Huang, Wei-Jan; Hsiao, George. 2019. "HDAC8 Inhibitor WK2-16 Therapeutically Targets Lipopolysaccharide-Induced Mouse Model of Neuroinflammation and Microglial Activation" Int. J. Mol. Sci. 20, no. 2: 410. https://doi.org/10.3390/ijms20020410

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