Abstract
Paraquat has dopaminergic neurotoxicity and potentially contributes to Parkinson's disease (PD) as a risk factor. However, the cellular and molecular mechanisms of PQ-induced neurodegeneration have not been clearly elucidated. Studies have shown that PQ induces microglial neuroinflammation through toll-like receptor 4 (TLR4)-nuclear factor-κB pathway, resulting in neuronal cell loss. Mitogen-activated protein kinases (MAPKs) are involved in the production of pro-inflammatory cytokines in microglia, and in this study, the role of MAPKs in PQ-activated microglial inflammation was investigated. Murine BV2 microglial cells were treated with 40 μM of PQ following pretreatment of the cells with selective inhibitor of MAPKs phosphorylation for blockage of the phosphorylation of ERK, JNK and P38, or a specific TLR4 inhibitor for blocking the activation of TLR4. The protein expression of phosphorylated ERK, JNK and p38, and the transcription expression of pro-inflammatory mediators were assessed with Western blotting and qRT-PCR technique, respectively. The results indicated that PQ significantly induced the phosphorylation of ERK, JNK and P38 in microglia, while MAPKs inhibitors suppressed PQ-induced phosphorylation of ERK, JNK and P38, and reduced the transcription level of pro-inflammatory cytokines. PQ-stimulated phosphorylation of ERK, JNK and P38 was also reduced by TLR4 inhibitor. The inhibited intensity in the level of pro-inflammatory cytokine transcription was obviously greater in TLR4 inhibitor + PQ group than in each MAPK inhibitor + PQ group. Taken together, inhibition of MAPKs phosphorylation partially attenuates PQ-induced microglial inflammation, which may become a potential intervention strategy for PQ neurotoxicity.