Abstract
Excessive microglial cells activation in response to inflammatory stimuli leads to synaptic loss, dysfunction, and neuronal cell death. Activated microglia are involved in the pathogenesis of neurological conditions and frequently contribute to several complications. Accumulating evidence suggests that signaling through PAR-1 is involved in inflammation, however, its function has yet to be fully elucidated. Here, we have demonstrated that the suppression of PAR-1 leads to down-regulation of inflammatory factors including IL-1β, IL-6, TNF-α, NO, as well as the prevention of activation of NF-κB in BV2 cells. In addition, we found that a PAR-1 antagonist, SCH, prevented LPS-induced excessive microglial activation in a dose-dependent manner. As a result of SCH treatment, neuronal cell death via up-regulation of Akt-mediated pathways was reduced. Our results demonstrate that the beneficial effects of SCH are linked to its ability to block an inflammatory response. Further, we found that SCH inhibited the death of PC12 neurons from the cytotoxicity of activated BV2 cells via activation of the PI3K/Akt pathway. These neuro-protective effects appear to be related to inhibition of PAR-1, and represents a novel neuroprotective strategy that could has potential for use in therapeutic interventions of neuroinflammatory disease.
Highlights
Involved in regulating expression of proinflammatory mediators, including cytokines, chemokines, and adhesion molecules, thereby playing a crucial role in mediating inflammatory responses[12,13]
protease-activated receptors (PARs)-1 has been shown to be involved in several brain pathologies, such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, stroke, and human immunodeficiency virus-associated dementia[31,32,33], suggesting its potential role in the regulation of brain function and the pathogenesis of these pathological changes
Our study demonstrated that the selective protease-activated receptor 1 (PAR-1) antagonist SCH suppresses excessive microglial activation and subsequent neuronal death in a cell culture-based neuroinflammation model
Summary
Involved in regulating expression of proinflammatory mediators, including cytokines, chemokines, and adhesion molecules, thereby playing a crucial role in mediating inflammatory responses[12,13]. Previous studies have demonstrated that thrombin, a pluripotent serine protease plays a critical role in hemostasis and coagulation. PAR-1 has been implied in a variety of CNS physiological processes depending on the activate serine protease and its target cell type[15]. While the effect of PAR-1 activation on cell survival and proliferation has been demonstrated in microglia[15], little is known regarding its role in modulating microglia-mediated inflammatory responses effects on neural cells. 2) whether SCH imposes an anti-inflammatory effects against lipopolysaccharide (LPS)-stimulated inflammatory responses in BV2 cells to protect PC12 neurons, and 3) the downstream effectors involved. We discovered that a key signaling enzyme implicated in cell survival[24], phosphatidylinositol 3-kinase (PI3K), is involved in the protection offered by PAR-1. The combined effect of LY29004 (Ly), a PI3K/Akt inhibitor[25], and SCH was investigated
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