Nilotinib inhibits microglia-mediated neuroinflammation to protect against dopaminergic neuronal death in Parkinson's disease models.

Abstract

Microglia-mediated neuroinflammation is tightly correlated with the etiology and progression of neurodegenerative disorders, including Parkinson's disease (PD). Nilotinib, a c-Abl inhibitor used for chronic myeloid leukemia, has been proven effective in relieving PD progression. However, whether nilotinib could affect neuroinflammation is largely unknown. In this current study, we investigated the role of nilotinib in microglia-mediated neuroinflammatory response in Parkinson's disease. Lipopolysaccharide (LPS)-induced neuroinflammation in BV2 microglial cells and mouse brains were used as models for Parkinson's disease. Our results demonstrated that nilotinib significantly suppressed LPS-induced neuroinflammation by reducing the production of pro-inflammatory factors including iNOS, COX-2, IL-1β, IL-6 and TNF-α in BV2 cells. Moreover, pretreatment of nilotinib attenuated the neurotoxicity of LPS-treated microglial conditioned medium to MES23.5 dopaminergic (DA) neurons. Mechanismly, nilotinib inhibited NF-κB signaling pathway and suppressed the nuclear translocation of p65 upon LPS stimulation. In LPS-injected mouse brains, nilotinib administration markedly suppressed the activation of microglia and down-regulated COX-2 as well as IL-1β expression. Most importantly, nilotinib effectively protected against microglial activation-mediated mouse DA neuronal loss. Taken together, our study suggests that nilotinib exerts anti-neuroinflammatory effect and protects DA neurons from activated microglia-induced inflammatory damage through suppressing NF-κB signaling pathway, indicating its potential application in further clinical trials.

• Authors: Jiayuan Wu, Xinqin Xu, Li Zheng, Juanfen Mo, Xiuhui Jin, Yi Bao
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 99 Pg. 108025 (Oct 2021) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 34364303 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Lipopolysaccharides
• Pyrimidines
• nilotinib

Topics

• Animals
• Apoptosis (drug effects, immunology)
• Brain (cytology, drug effects, immunology, pathology)
• Cell Line
• Disease Models, Animal
• Dopaminergic Neurons (drug effects, immunology, pathology)
• Humans
• Lipopolysaccharides (immunology)
• Male
• Mice
• Microglia (drug effects, immunology, pathology)
• Neuroinflammatory Diseases (drug therapy, immunology, pathology)
• Parkinson Disease (drug therapy, immunology, pathology)
• Pyrimidines (pharmacology, therapeutic use)
• Signal Transduction (drug effects)