Abstract
Microglia-induced neuroinflammation is an important pathological mechanism influencing various neurodegenerative disorders. Excess activation of microglia produces a myriad of proinflammatory mediators that decimate neurons. Hence, therapeutic strategies aimed to suppress the activation of microglia might lead to advancements in the treatment of neurodegenerative diseases. In this study, we synthesized a novel ethyl pyruvate derivative, named EOP (S-ethyl 2-oxopropanethioate) and studied its effects on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) in rat primary microglia and mouse BV-2 microglia. EOP significantly decreased the production of NO, inducible nitric oxide synthase, cyclooxygenase and other proinflammatory cytokines, such as interleukin (IL)-6, IL-1β and tumor necrosis factor-α, in LPS-stimulated BV-2 microglia. The phosphorylation levels of extracellular regulated kinase, p38 mitogen-activated protein kinase, and nuclear translocation of NF-κB were also inhibited by EOP in LPS-activated BV-2 microglial cells. Overall, our observations indicate that EOP might be a promising therapeutic agent to diminish the development of neurodegenerative diseases associated with microglia activation.
Highlights
The central nervous system (CNS) has been assumed to be an immunologically-restricted organ because the blood-brain barrier eliminates most of the components of the immune system and thereby limits its inflammatory capacity and prevents lymphatic infiltration [1]
2-oxopropanoyl chloride 2 was reacted with ethanethiol to produce the crude product, which was purified by silica gel chromatography with dichloromethane to give ethyl 2-oxopropanethioate (EOP)
Based on earlier reports that proinflammatory cytokines released from microglia are necessary for neuronal cell death [36], we examined the effects of EOP on suppressing the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), IL-6 and IL-1β, in BV-2 microglia
Summary
The central nervous system (CNS) has been assumed to be an immunologically-restricted organ because the blood-brain barrier eliminates most of the components of the immune system and thereby limits its inflammatory capacity and prevents lymphatic infiltration [1]. In pathologies related to the CNS, EP attenuates kainic acid-induced neuronal cell death in the mouse hippocampus [15], confers potent neuroprotection against neonatal H-I brain injury via its anti-cell death and anti-inflammatory actions [16], protects PC12 cells against dopamine by modulating key signaling pathways of apoptosis and inhibiting intercellular oxidative stress [17] and protects nigrostriatal dopaminergic neurons by modulating activation of glia in a mouse model of Parkinson’s disease [18]. A subsequent examination of molecular pathways revealed that the anti-neuroinflammatory activity of EOP occurred by inhibiting phosphorylation of p38 and extracellular regulated kinase-mitogen activated protein kinase (ERK-MAPK) and by suppressing nuclear levels of the nuclear factor (NF)-κB p65 subunit in LPS-stimulated BV-2 cells. Widen our understanding of the anti-neuroinflammatory effects of EOP and suggest a possible new pharmacological agent for treating neuroinflammatory diseases
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