RRx-001 Exerts Neuroprotection Against LPS-Induced Microglia Activation and Neuroinflammation Through Disturbing the TLR4 Pathway
Neuroinflammation plays a huge role within the pathogenesis of numerous nervous system illnesses. Here, we investigated the result of the anti-cancer compound RRx-001 on neuroinflammation and it is possible new applications. BV2 cells and first microglia cells were utilised to judge the function of RRx-001 in LPS-caused microglial activation and inflammatory response in vitro. And, we discovered that the rise in the synthesis and discharge of cytokines and also the up-regulating pro-inflammatory factors in LPS-treated microglial cells were considerably reduced by RRx-001 pretreatment. Because the most classical inflammatory pathways, NF-?B and MAPK signaling pathways were activated by LPS, but were inhibited by RRx-001. Transcription of NLRP3 seemed to be reduced by RRx-001. Additionally, LPS caused oxidative stress by growing the expression of Nox mediated by transcription factors NF-?B and AP-1, while RRx-001 pretreatment ameliorated Nox-mediated oxidative stress. LPS-caused activation of TAK1, an upstream regulator of NF-?B and MAPK pathways, was considerably inhibited by RRx-001 pretreatment, whereas recruitment of MyD88 to TLR4 wasn’t impacted by RRx-001.
LPS-primed BV2 condition medium caused RRx-001 injuries of primary neurons, which effect was inhibited by RRx-001. In addition, we established a neuroinflammatory mouse model by stereotactic injection of LPS in to the substantia nigra pars compacta (SNpc), and RRx-001 dose-dependently reduced LPS-caused microglial activation and lack of TH neurons within the midbrain. To conclude, the present study discovered that RRx-001 covered up microglia activation and neuroinflammation through targeting TAK1, and can be a candidate to treat neuroinflammation-related brain illnesses.