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-1ß, 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-1ß 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.
Subject(s)
Dopaminergic Neurons/drug effects , Microglia/drug effects , Neuroinflammatory Diseases/drug therapy , Parkinson Disease/drug therapy , Pyrimidines/pharmacology , Animals , Apoptosis/drug effects , Apoptosis/immunology , Brain/cytology , Brain/drug effects , Brain/immunology , Brain/pathology , Cell Line , Disease Models, Animal , Dopaminergic Neurons/immunology , Dopaminergic Neurons/pathology , Humans , Lipopolysaccharides/immunology , Male , Mice , Microglia/immunology , Microglia/pathology , Neuroinflammatory Diseases/immunology , Neuroinflammatory Diseases/pathology , Parkinson Disease/immunology , Parkinson Disease/pathology , Pyrimidines/therapeutic use , Signal Transduction/drug effectsABSTRACT
Genetic resources available for Arabidopsis thaliana make this species particularly attractive as a model for molecular genetic studies of guard cell homeostasis, transport and signalling, but this facility is not matched by accessible tools for quantitative analysis of transport in the intact cell. We have developed a reliable set of procedures for voltage clamp analysis of guard cells from Arabidopsis leaves. These procedures greatly simplify electrophysiological recordings, extending the duration of measurements and scope for analysis of the predominant K+ and anion channels of intact stomatal guard cells to that achieved previously in work with Vicia and tobacco guard cells.
