Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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A Novel Pyrazolo[3,4-d]pyrimidine Induces Heme Oxygenase-1 and Exerts Anti-Inflammatory and Neuroprotective Effects

  • Lee, Ji Ae (Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine) ;
  • Kwon, Young-Won (Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine) ;
  • Kim, Hye Ri (Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine) ;
  • Shin, Nari (Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine) ;
  • Son, Hyo Jin (Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine) ;
  • Cheong, Chan Seong (Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology) ;
  • Kim, Dong Jin (Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology) ;
  • Hwang, Onyou (Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine)
  • Received : 2021.03.26
  • Accepted : 2021.10.15
  • Published : 2022.03.31
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Abstract

The anti-oxidant enzyme heme oxygenase-1 (HO-1) is known to exert anti-inflammatory effects. From a library of pyrazolo[3,4-d]pyrimidines, we identified a novel compound KKC080096 that upregulated HO-1 at the mRNA and protein levels in microglial BV-2 cells. KKC080096 exhibited anti-inflammatory effects via suppressing nitric oxide, interleukin1β (IL-1β), and iNOS production in lipopolysaccharide (LPS)-challenged cells. It inhibited the phosphorylation of IKK and MAP kinases (p38, JNK, ERK), which trigger inflammatory signaling, and whose activities are inhibited by HO-1. Further, KKC080096 upregulated anti-inflammatory marker (Arg1, YM1, CD206, IL-10, transforming growth factor-β [TGF-β]) expression. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinetreated mice, KKC080096 lowered microglial activation, protected the nigral dopaminergic neurons, and nigral damage-associated motor deficits. Next, we elucidated the mechanisms by which KKC080096 upregulated HO-1. KKC080096 induced the phosphorylation of AMPK and its known upstream kinases LKB1 and CaMKKbeta, and pharmacological inhibition of AMPK activity reduced the effects of KKC080096 on HO-1 expression and LPS-induced NO generation, suggesting that KKC080096-induced HO-1 upregulation involves LKB1/AMPK and CaMKKbeta/AMPK pathway activation. Further, KKC080096 caused an increase in cellular Nrf2 level, bound to Keap1 (Nrf2 inhibitor protein) with high affinity, and blocked Keap1-Nrf2 interaction. This Nrf2 activation resulted in concurrent induction of HO-1 and other Nrf2-targeted antioxidant enzymes in BV-2 and in dopaminergic CATH.a cells. These results indicate that KKC080096 is a potential therapeutic for oxidative stress-and inflammation-related neurodegenerative disorders such as Parkinson's disease.

Keywords

Acknowledgement

This research was funded by the National Research Foundation of Korea (2009-0081674,5 & 2018R1A6A3A01010564), Republic of Korea.

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