| Parkinson's disease (PD) is one of the major neurodegenerative disorders, characterized by a progressive and selective degeneration of nigrostriatal dopaminergic pathway, which results in movement dysfunction. Its cardinal clinical symptoms include bradykinesia, rigidity, rest tremor and disturbances in balance. Despite decades of intensive research, the etiology of idiopathic PD, which accounts for > 90% of PD, and the pathogenesis of PD remain unclear, which has significantly hampered the development of effective therapeutic strategies to halt the progression of this devastating disease. Thus, at the present time, therapeutic interventions such as dopamine replacement treatment are essentially symptomatic, which fail to halt the degenerative process. In addition, the decline of the efficacy and the occurrence of severe side effects after long-term use of dopaminergic drugs make it urgent to develop more effective therapeutic strategies aiming at halting the natural progression of PD. The prerequisite for success in developing effective strategies is to understand the specific etiology and the nature of the pathogenesis of PD. Recently, increasing evidence suggested the involvement of multiple environmental factors in the initiation and/or progression of PD. Among these potential environmental risk factors, inflammation in the brain, also named by neuroinilammation has long been suspected to be involved in the pathogenesis of PD. In the present study, we explored the role for neuroinflammation in several in vivo and in vitro PD models. More importantly, taking advantage of cell culture systems, we further studied the mechanism of action responsible for the selective and progressive dopaminergic neurodegeneration induced by neuroinflammation.1. Neuroinflammation induced by the inflammogen lipopolysaccharide (LPS) can directly initiate dopaminergic neurodegeneration.This study demonstrated that chronic infusion of LPS at 5 ng/h for 2 weeks into rat substantia nigra (SN) triggered a rapid activation of microglia that reached a plateau within 2 weeks, followed by a delayed and gradual loss of nigral dopaminergic neurons that began to occur between 4-6 weeks and reached 70% by 10 weeks. Simultaneous quantification of tyrosine hydroxylase-immunoreactive (TH-IR) neurons and neuron-specific nuclear protein-immunoreactive (Neu-N-IR) neurons, which represents dopaminergic neurons and neurons in general, respectively, showed that LPS-induced neurotoxicity appeared to be preferential to dopaminergic neurons. Confocal double-label (TH and Neu-N) immunofluorescent analysis confirmed the selectivity of LPS-induced neurotoxicity. Further investigation of the underlying mechanism of action of microglia-mediated neurotoxicity using rat mesencephalic neuron-glia cultures illustrated that LPS (0.1-10 ng/ml)-induced microglial activation and production of neurotoxic factors preceded the progressive and selective degeneration of dopaminergic neurons.Microglia, the resident immune cells in the brain, play a role of immune surveillance under normal conditions. However, microglia become readily activated in response to injuries in the brain and immunological challenges. Activated microglia are believed to exert the neurotoxic effect primarily through releasing a wide array of pro-inflammatory or cytotoxic factors, including tumor necrosis factor-a (TNF-a), interleukin-lp (CL-lp), eicosanoids, nitric oxide (NO), and reactive oxygen species (ROS), which impact on neurons to induce neurodegeneration. Among these factors produced by activated microglia, the NADPH oxidase-mediated release of superoxide appeared to be a predominant effector of LPS-induced neurodegeneration, consistent with the notion that dopaminergic neurons are particularly vulnerable to oxidative insults. This is the first report that microglial activation induced by chronic exposure to inflammogen was capable of inducing a delayed and selective degeneration of nigral dopaminergic neurons and that microglia-originated free radicals play a pi...
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