期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/ijms23084420
关键词
alpha 7 nAChR agonist; GTS-21; microglia; neuroinflammation; Parkinson's disease; molecular mechanism
资金
- National Research Foundation of Korea (NRF) - Korean government (MSIT) [NRF-2021R1A2C1006369, NRF-2020R1A5A2019210]
This study examined the anti-inflammatory and neuroprotective effects of GTS-21, a selective alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) agonist, in neuroinflammation and Parkinson's disease (PD) mouse models. GTS-21 inhibited inflammation by reducing the expression of pro-inflammatory cytokines and activating anti-inflammatory signaling pathways. It also showed neuroprotective properties by reducing microglial activation and protecting dopaminergic neurons.
Neuroinflammation is crucial in the progression of neurodegenerative diseases. Thus, controlling neuroinflammation has been proposed as an important therapeutic strategy for neurodegenerative disease. In the present study, we examined the anti-inflammatory and neuroprotective effects of GTS-21, a selective alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) agonist, in neuroinflammation and Parkinson's disease (PD) mouse models. GTS-21 inhibited the expression of inducible nitric oxide synthase (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-kappa B, and upregulating AMPK, Nrf2, CREB, and PPAR gamma signals. The effects of GTS-21 on these pro-/anti-inflammatory signaling molecules were reversed by treatment with an alpha 7 nAChR antagonist, suggesting that the anti-inflammatory effects of GTS-21 are mediated through alpha 7 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.
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