| Microglia are the resident immune cells in the brain, in mature brains, Resting microglia exhibit a characteristic ramified morphology and serve the critical role of immune surveillance. As an important line of defense in the brain, microglia become readily activated in reponse to injuries to the brain or to the immunologic stimuli. Activated microglia undergo dramatic morphologic changes, metamorphosing from resting ramified microglia into activated amoeboid microglia. They also exhibit increased expression of surface molecules such as complement receptor sand major histocompatibility complex (MHC) molecules. At the same time, Activated microglia release a variety of soluble factors. Although activated microglia are knovra to produce several trophic factors, most of the factors relased by activated microglia are proinflammatory and potentially cytotoxic. Several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are associated with immunocompetent microglia, leading to the suggestion that chronic glial-mediated inflammation contributes to the neurodegeneration seen in these diseases. Add A β or LPS in neuron-glia cell cultures, activated microglia release variety of proinflammatory factors including TNF α ,interleukin-1β, nitric oxide and superoxide. Superoxide is the earliest one among these proinflammatory factors. So the effect of superoxide on neurodegeneration can not be undervalued. In this study, using A β or LPS, we investigated the important role of superoxide generated from NADPH oxidase in the activation of microgli. We also demonstrated that DM and Naloxone significantly reduce the production of superoxide. This afford the strategy for the treatment of nerodegenerative dease.　. Microglia enhance A β -induced toxicity in cortical and mesencephalic neurons: The purpose of this study was to assess and compare, for the first time, the toxicity of Aβ on primary cortical and mesencephalic neurons cultured with and without microglia in an effort to determine the mechanism for microglia-mediated Ap-induced neurotoxicity. Incubation of cortical or mesencephalic neuron-enriched and mixed neuron-glia cultures with Aβ (1-42) over the concentration range of 0.1-6.0μM caused a concentration-dependent neurotoxicity. High concentrations of Aβ (6.0 μM for cortex and 1.5-2.0 μM for mesencephalon) directly injured neurons in neuron-enriched cultures. In contrast, lower concentrations of Aβ (1.0-3.0 μM for cortex and 0.25-1.0 μM for mesencephalon) caused significant neurotoxicity in the mixed neuron-glia cultures, but not in the neuron-enriched cultures. Several lines of evidence are provided that microglia mediated the potentiated neurotoxicity of Aβ including: low concentrations of Aβ activated microglia morphologically in neuron-glia cultures; and addition of microglia to cortical neuron-glia cultures enhanced Aβ-induced neurotoxicity. To search for the mechanism underlying the microglia mediated effects, several proinflammatory factors were determined in neuron-glia cultures. Low doses of Aβ significantly increased the production of superoxide anions, but not tumor necrosis factor α, interleukin-1β, or nitric oxide. Catalase and superoxide dismutase significantly protected neurons from Aβ toxicity in the presence of microglia. Furthermore, inhibition of NADPH oxidase activity by diphenyleneiodonium also prevented Aβ-induced neurotoxicity in neuron-glia mixed cultures. This study demonstrates that one of the mechanisms by which microglia can enhance the neurotoxicity of Aβ is via the production of reactive oxygen species.2. Inhibition by naloxone stereoisomers of Aβ-induced superoxide production in microglia and degeneration of cortical and mesencephalic neurons: Previously we reported that naloxone stereoisomers, in an opioid receptor-independent manner, prevented the infiammagen-induced degeneration of dopaminergic neurons by inhibition of the activation of microglia, the resident immune cells in the brain.Recently we discovered that beta-amyloid pepti...
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