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Involvement of 5-lipoxygenase/cysteinyl leukotriene receptor 1 in rotenone- and MPP+-induced BV2 microglial activation
Molecular Neurodegeneration volume 7, Article number: S24 (2012)
Neuroinflammation plays a prominent role in the pathogenesis of Parkinson’s disease (PD), and microglial activation contributes to initiating and maintaining brain inflammation and neuronal death. 5-Lipoxygenase (5-LOX) is a key enzyme catalyzing arachidonic acid to produce cysteinyl leukotrienes (CysLTs). CysLTs are potent proinflammatory mediators, and their actions are mediated by activating CysLT receptors. We recently reported that rotenone time- and concentration-dependently induced 5-LOX translocation into the nuclear envelope (a key event for 5-LOX activation) and cell injury in PC12 cells, and the 5-LOX selective inhibitor zileuton attenuated rotenone-induced 5-LOX activation and cell injury. To determine the role of 5-LOX pathway in microglial-dependent neuroinflammation, we investigated the changes of 5-LOX and CysLT1 receptor in a cell model of PD induced by specific mitochondrial complex I inhibitors (rotenone or 1-methyl-4-phenylpyridinium (MPP+)) in BV2 microglial cells.
BV2 cells, a murine BV2 microglia cell line, were cultured in media with or without rotenone (0.1, 0.3, 1, 3, 10 nM) or MPP+ (0.003, 0.01, 0.03, 0.1, 0.3 μM) for 24 h. The number of microglia was counted. Phagocytotic activity of BV2 cells was evaluated using fluorescent microspheres. Expression and translocation of 5-LOX and CysLT1 receptor were detected by immunocytochemical analysis.
The low doses of rotenone (1-10 nM) or MPP+ (0.03-0.3 μM) induced cell proliferation and microglial phagocytosis in BV2 cells. The number of BV2 cells was significantly increased after 24 h treatment with 1 nM rotenone or 0.03-0.1 μM MPP+. After treatment with 1-10 nM rotenone or 0.01-0.3 μM MPP+, phagocytosis was significantly increased in BV2 cells. Furthermore, we found that 5-LOX expression was increased in a time-dependent manner, and 5-LOX was primarily localized in the nuclear envelope and cytoplasm, and a plaque-like distribution was found in the nucleus in rotenone (3 nM)-activated BV2 cells. In addition, MPP+ (0.003-0.3 μM) concentration-dependently induced CysLT1 receptor translocation from cell membrane to the cytoplasm.
These results suggest an involvement of the 5-LOX/CysLT1 receptor in rotenone- and MPP+-induced BV2 microglial activation. The 5-LOX signaling pathway might therefore be a potential therapeutic target for modulating microglial-mediated inflammation of PD.
Supported by Zhejiang Provincial Education Department Science Foundation of China (Y200907625), Hangzhou Key Laboratory Research Program of china (20090233T12), and Hangzhou Normal University Science Foundation of china (2010PYjj41).
Yanfang Wang, Xiaoyan Zhang contributed equally to this work.
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Wang, Y., Zhang, X., Li, C. et al. Involvement of 5-lipoxygenase/cysteinyl leukotriene receptor 1 in rotenone- and MPP+-induced BV2 microglial activation. Mol Neurodegeneration 7, S24 (2012). https://doi.org/10.1186/1750-1326-7-S1-S24
- CysLT1 Receptor
- Inhibitor Zileuton
- Potent Proinflammatory Mediator