Inhibitory effects of betulinic acid on LPS-induced neuroinflammation involve M2 microglial polarization via CaMKKβ-dependent AMPK activation

Chuwen Li, Chao Zhang, Hefeng Zhou, Yu Feng, Fan Tang, Maggie P.M. Hoi, Chengwei He, Dan Ma, Chao Zhao, Simon M.Y. Lee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


In response to the microenvironment, microglia may polarize into either an M1 pro-inflammatory phenotype, exacerbating neurotoxicity, or an M2 anti-inflammatory phenotype, conferring neuroprotection. Betulinic acid (BA) is a naturally pentacyclic triterpenoid with considerable anti-inflammatory properties. Here, we aim to investigate the potential effects of BA on microglial phenotype polarization and to reveal the underlying mechanisms of action. First, we confirmed that BA promoted M2 polarization and inhibited M1 polarization in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Then, we demonstrated that the effect of BA on microglial polarization was dependent on AMP-activated protein kinase (AMPK) activation, as evidenced by the fact that both AMPK inhibitor compound C and AMPK siRNA abolished the M2 polarization promoted by BA. Moreover, we found that calmodulin-dependent protein kinase kinase β (CaMKKβ), but not liver kinase B1, was the upstream kinase required for BA-mediated AMPK activation and microglial M2 polarization, via the use of both the CaMKKb inhibitor STO-609 and CaMKKβ siRNA. Finally, BA enhanced AMPK phosphorylation and promoted M2 microglial polarization in the cerebral cortex of LPSinjected mice brains, which was attenuated by pre-administration of the AMPK inhibitor. This study demonstrated that BA promoted M2 polarization of microglia, thus conferring anti-neuroinflammatory effects via CaMKKβ-dependent AMPK activation.

Original languageEnglish
Article number98
JournalFrontiers in Molecular Neuroscience
Publication statusPublished - 3 Apr 2018

Bibliographical note

© 2018 Li, Zhang, Zhou, Feng, Tang, Hoi, He, Ma, Zhao and Lee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Funding Information:
This study was supported by grants from The Science and Technology Development Fund (FDCT) Fundo para o Desenvolvimento das Ciências e da Tecnologia 501100006469 of Macao SAR


  • AMP-activated protein kinase
  • Betulinic acid
  • Calmodulin-dependent protein kinase β
  • Microglia polarization
  • Neuroinflammation


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