Anti-Inflammatory and Neuroprotective Mechanisms of GTS-21, an α7 Nicotinic Acetylcholine Receptor Agonist, in Neuroinflammation and Parkinson’s Disease Mouse Models

Jung Eun Park, Yea Hyun Leem, Jin Sun Park, Do Yeon Kim, Jihee Lee Kang, Hee Sun Kim

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Neuroinflammation is crucial in the progression of neurodegenerative diseases. Thus, con-trolling neuroinflammation has been proposed as an important therapeutic strategy for neurodegener-ative disease. In the present study, we examined the anti-inflammatory and neuroprotective effects of GTS-21, a selective α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, in neuroinflammation and Parkinson’s disease (PD) mouse models. GTS-21 inhibited the expression of inducible nitric oxide syn-thase (iNOS) and proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and primary microglia. Further research revealed that GTS-21 has anti-inflammatory properties by inhibiting PI3K/Akt, NF-κB, and upregulating AMPK, Nrf2, CREB, and PPARγ signals. The effects of GTS-21 on these pro-/anti-inflammatory signaling molecules were reversed by treatment with an α7 nAChR antagonist, suggesting that the anti-inflammatory effects of GTS-21 are mediated through α7 nAChR activation. The anti-inflammatory and neuroprotective properties of GTS-21 were then confirmed in LPS-induced systemic inflammation and MPTP-induced PD model mice. In LPS-injected mouse brains, GTS-21 reduced microglial activation and production of proinflammatory markers. Furthermore, in the brains of MPTP-injected mice, GTS-21 restored locomotor activity and dopaminergic neuronal cell death while inhibiting microglial activation and pro-inflammatory gene expression. These findings suggest that GTS-21 has therapeutic potential in neuroinflammatory and neurodegenerative diseases such as PD.

Original languageEnglish
Article number4420
JournalInternational Journal of Molecular Sciences
Volume23
Issue number8
DOIs
StatePublished - 1 Apr 2022

Keywords

  • GTS-21
  • microglia
  • molecular mechanism
  • neuroinflammation
  • Parkinson’s disease
  • α7 nAChR agonist

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