Src Inhibition Attenuates Neuroinflammation and Protects Dopaminergic Neurons in Parkinson’s Disease Models

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.

Proto-oncogene tyrosine-protein kinase SRC (Src) inhibition in microglia relieves neuroinflammation in neuropathic pain mouse models

“…All above studies showed Src is a crucial factor involving in neuroinflammatory development. In our study, we found that Src expression was significantly increased in LPS-induced BV2 microglia and spinal cords of PNL-treated mice; besides, we demonstrated that p-Src after PP2 treatment was significantly reduced in both in vitro and in vivo studies, which was consistent with the results in mouse brain treated with PP2 in a previous study [ 28 ]. In vitro , LPS-induced microglia treated with PP2 showed lower activation and infiltration ability accompanied by alleviated neuroinflammation.…”

“…Recently, a study suggested that LDL receptor-related protein-1 deficiency in microglia could block neuroinflammation and attenuate NP processing [ 27 ]. For the past few years, Src has been reported to be closely related to searching treatment for blocking neuroinflammation [ 28 , 29 ]. Socodato and his workmates found that Src played a key role in triggering microglial activation [ 20 ].…”

“…Additionally, Src/ERK signaling provoked inspiratory resistive breathing induced acute lung injury and inflammation [ 30 ]. Yang et al [ 28 ] suggested that regulating Src signaling pathway may reduce microglia-induced neuroinflammation in Parkinson’s disease. All above studies showed Src is a crucial factor involving in neuroinflammatory development.…”

Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model

“…SAR is an inhibitor of Src family tyrosine kinases (SFKs) which are implicated in several developmental, neuroinflammatory, and synaptic plasticity pathways (Ingraham et al, 1989;Boggon and Eck, 2004;Ohnishi et al, 2011;Nie et al, 2020;Gage and Thippeswamy, 2021). SFKs have been implicated in a variety of neurological diseases, including Parkinson's and Alzheimer's diseases (PD, AD), stroke, chronic pain and epilepsy (Lee et al, 2004;Kaufman et al, 2015;Knox and Jiang, 2015;Miyamoto et al, 2017;Sharma et al, 2018Sharma et al, , 2021Panicker et al, 2019;Ge et al, 2020;Yang et al, 2020). In neurons, phosphorylated Fyn, a SFK, interacts with tau in response to seizures and can lead to phosphorylation of N-methyl D-aspartate receptors (NMDAR) and contribute to glutamatergic toxicity (Nakazawa et al, 2001;Yang and Leonard, 2001;Ittner et al, 2010;Trepanier et al, 2012;Putra et al, 2020b).…”

The role of circadian rhythm in the regulation of cellular protein profiles in the brain

“…It is responsible for development of B-cell and involved in B-cell receptor signaling [27,28]. In addition, it is predicted that SRC is a non-receptor tyrosine kinase that plays an important role in the Parkinson's disease which is the second most common neurodegenerative disorders after Alzheimer's disease [29]. PSMB6 also known as 20S proteasome subunit beta-1 which codes for the β1 core catalytic subunit of the proteasome [30].…”