The Regulation Of Microglia Activation By Rotenone

Parkinson’s disease is a common neurodegenerative disease. It affects almost1%within the population at65years old. It was characterized by a selective and progressive loss of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc). And the depigmentation is also observed in the SNpc of the Parkinson’s disease. Due to depletion of dopamine within the striatum, the motor circuits were dysregulated. This would finally result in the clinical manifestations of Parkinson’s disease, like resting tremor, muscular rigidity and bradykinesia.Although the etiology of Parkinson’s disease is still not fully understood, there are many research suggested that the genes mutation and environment toxins play a role in the pathogenesis of Parkinson’s disease. There some genes were identified from the study with the rare familial forms of the Parkinson’s disease. These genes include a-synuclein, Parkin, PINK1, DJ1and LRRK2. At same time, the epidemiology studies have suggested that some environment toxins, like rotenone or paraquat, can induce parkinsonian syndrome in animal model. And the1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) can develop Parkinson disease in it-intoxicated patients finally. The drugs were the mitochondrial complex I inhibitors. They inhibited the activity of mitochondrial complex, induced over-loaded reactive oxygen species (ROS) and finally damaged the neurons.However, how these factors finally result in the degeneration of DA neurons in SNpc was not clear. But meanwhile, some studies have suggested that there may be another factors imply in the pathogenesis of Parkinson’s disease, like neuroinflammation. The neuroinflammation is a microglia-mediated inflammation in brian. The microglia are derived from myeloid cells and comprise approximately12%of cells in the brain. Under resting state, they act like macrophage to clear some toxic substance. And they also secrete some neurotrophic factors and anti-inflammatory factors. These were essential for neurons survival. However, once the microglia were sustained activated, they would produce some cytotoxic factors, like superoxide, tumour necrosis factor-a (TNFa) and nitric oxide (NO) and confer damage to neurons. Both the activated microglia and the increased inflammatory factors were detected in the SNpc of Parkinsons’s disease. And consistently, the risk of Parkinson’s disease in the population taking nonsteroidal anti-inflammatory drugs was significant decreased. These suggested that the neuroinflammation play an import role in the pathogenesis of Parkinsons’s disease.Thus, to uncover the mechanism about the microglia activation is meaningful for Pakinson’s disease. There were research suggested that the serious neuronal damage may induce the neuroinflammation, as the some inducer may release from the damaged neurons. Recent studies found that the microglia was activated when the neurons damaged was not obviously observed, suggesting that the microglia activation implies in the neurodegeneration process.In present study, we found that the rotenone, a mitochondrial complex I inhibitor, can direct induce microglia activation. The rotenone induces NF-κB signal pathway activation and profoundly inflammatory factor production in microglia cells. And the NF-κB signal pathway activation is dependent on the MAPK (p38). Rotenone inhibits the mitochondrial complex I and induces reactive oxygen species (ROS) production. The increases ROS finally can induce the p38activation. And to eliminate the ROS can block the rotenone induced-NF-κB signal pathway and microglia activation. Together, we study reveal that the rotenone directly induces microglia activation. And this effect may promote the rotenone-induced DA neurons loss.