Exp Neurobiol.  2018 Oct;27(5):408-418. 10.5607/en.2018.27.5.408.

The Novel Neuroprotective Compound KMS99220 Has an Early Anti-neuroinflammatory Effect via AMPK and HO-1, Independent of Nrf2

Affiliations
  • 1Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 05505, Korea. oyhwang@amc.seoul.kr
  • 2Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.
  • 3Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Korea.
  • 4Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea.

Abstract

We have previously reported a novel synthetic compound KMS99220 that prevented degeneration of the nigral dopaminergic neurons and the associated motor deficits, suggesting a neuroprotective therapeutic utility for Parkinson's disease. Microglia are closely associated with neuroinflammation, which plays a key role in the pathogenesis of neurodegenerative diseases. In this study, we investigated the effects of KMS99220 on the signaling involving AMP-activated protein kinase (AMPK) and heme oxygenase-1 (HO-1), the enzymes thought to regulate inflammation. KMS99220 was shown to elevate the enzyme activity of purified AMPK, and phosphorylation of cellular AMPK in BV2 microglia. It increased the level of HO-1, and this was attenuated by AMPK inhibitors. KMS99220 lowered phosphorylation of IκB, nuclear translocation of NFκB, induction of inducible nitric oxide synthase, and generation of nitric oxide in BV2 cells that had been challenged with lipopolysaccharide. This anti-inflammatory response involved HO-1, because both its pharmacological inhibition and knockdown of its expression abolished the response. The AMPK inhibitors also reversed the anti-inflammatory effects of KMS99220. The induction of HO-1 by KMS99220 occurred within 1 h, and this appeared not to involve the transcription factor Nrf2, because Nrf2 knockdown did not affect the compound's HO-1 inducing- and anti-inflammatory effects in this time window. These findings indicated that KMS99220 leads to AMPK-induced HO-1 expression in microglia, which in turn plays an important role in early anti-inflammatory signaling. Together with its neuroprotective property, KMS99220 may serve as a feasible therapeutic agent against neuroinflammation and neurodegeneration.

Keyword

Microglia; Neuroinflammation; AMPK; HO-1; iNOS

MeSH Terms

AMP-Activated Protein Kinases*
Dopaminergic Neurons
Heme Oxygenase-1
Inflammation
Microglia
Neurodegenerative Diseases
Nitric Oxide
Nitric Oxide Synthase Type II
Parkinson Disease
Phosphorylation
Transcription Factors
AMP-Activated Protein Kinases
Heme Oxygenase-1
Nitric Oxide
Nitric Oxide Synthase Type II
Transcription Factors
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