HDAC8 inhibitor WK2-16 therapeutically targets lipopolysaccharide-induced mouse model of neuroinflammation and microglial activation

Fan Li Lin, Jing Lun Yen, Yu Cheng Kuo, Jaw Jou Kang, Yu Wen Cheng, Wei Jan Huang, George Hsiao

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number410
Pages (from-to)410
JournalInternational Journal of Molecular Sciences
Volume20
Issue number2
DOIs
Publication statusPublished - Jan 2 2019

Keywords

  • Akt
  • HDAC8 inhibitor
  • Microglia
  • Neuroinflammation
  • STAT
  • WK2-16

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint Dive into the research topics of 'HDAC8 inhibitor WK2-16 therapeutically targets lipopolysaccharide-induced mouse model of neuroinflammation and microglial activation'. Together they form a unique fingerprint.

  • Cite this