Abstract

Chronic neuroinflammation is of great importance in the pathogenesis of Parkinson’s disease (PD). During the process of neuroinflammation, overactivated microglia release many proinflammatory factors, which eventually induce neurodegeneration. Inhibition of excessive microglial activation is regarded as a promising strategy for PD treatment. Src is a non-receptor tyrosine kinase that is closely related to tumors. Recently, some reports indicated that Src is a central mediator in multiple signaling pathways including neuroinflammation. The aim of our study was to demonstrate the role of Src in microglial regulation and neuroinflammation. The lipopolysaccharide (LPS)-stimulated BV2 microglia model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model were applied in this study. The results showed that inhibition of Src could significantly relieve microgliosis and decrease levels of inflammatory factors. Besides, inhibition of Src function reduced the loss of dopaminergic neurons and improved the motor behavior of the MPTP-treated mice. Thus, this study not only verified the critical role of Src tyrosine kinase in neuroinflammation but also further proved that interfering neuroinflammation is beneficial for PD treatment. More importantly, this study shed a light on the hypothesis that Src tyrosine kinase might be a potential therapeutic target for PD and other neuroinflammation-related diseases.

Highlights

  • Parkinson’s disease (PD), an age-related progressive neurodegenerative disorder, is characterized by the degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc) and resultant depletion of dopamine in the striatum (Iliopoulos et al, 2009)

  • Cell viability experiment showed that PP2 at the concentration range of 2–20 μM did not have a toxic effect on cell viability in BV2 microglia with or without 1 μg/ml of LPS, whereas PP2 at 200 μM produced significant cytotoxicity (Supplementary Figure S1)

  • We reported the effect of Src inhibition on microglial activation and revealed the role of Src in neuroinflammation

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Summary

Introduction

Parkinson’s disease (PD), an age-related progressive neurodegenerative disorder, is characterized by the degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc) and resultant depletion of dopamine in the striatum (Iliopoulos et al, 2009). Positron emission tomography (PET) imaging of PD patients showed that the level of microglial activation and proinflammatory mediators are markedly elevated in the SNpc during post-mortem examinations (Mogi et al, 1994) These studies supported that neuroinflammation played a vital role in the loss of dopaminergic neurons and the exacerbation of the clinical symptoms. Several studies showed that there may be a protective effect of non-aspirin non-steroidal anti-inflammatory drug use in PD patients, consistent with the possible neuroinflammatory pathway in PD pathogenesis (Chen et al, 2005; Gao et al, 2011) These studies have supported the idea that inhibition of neuroinflammation through regulating microglial activation might be a therapeutic approach for PD treatment

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