**7. Conclusions**

340 Etiology and Pathophysiology of Parkinson's Disease

Lai and Todd (2008) examined the effect of microglia by changing the severity of hypoxiainduced neuronal injury in a culture study. After exposing neuronal cells to various degrees of hypoxia, i.e., mild, moderate, or severe, the media from the neuronal cell culture were added to microglial cell culture. Neuroprotective phenotype of microglia was observed with the media from neurons with moderate hypoxia, but not with those from the cultured cells

Fig. 5. This scheme shows a hypothesis of toxic change of microglia by two step activation of microglia proposed by Sawada M. et al. At the first step, activated microglia by the first stimulation probably by signaling molecules from injured neurons produce such as

neurotrophins, neurotrophic cytokines, antioxidant, and may act for neuroprotection. At the secondary step, activated microglia, which are further stimulated by other factors such as a large amount of cytotoxic factors, may produce toxic change of microglia, which converts

Inoue (2002) hypothesized that the fate of damaged neurons may be regulated in part by ATP through the activation of microglia. Microglia possess the functional P2 receptors, P2X and P2Y, which bind to purines and pyrimidines. Microglial activation is triggered by extracellular ATP or ADP, which is released from damaged neurons under pathological situations. Microglia showed membrane ruffling and enhanced chemotaxis in response to extracellular ATP or ADP produced by neuronal injuries (Honda et al., 2001). A low concentration of extracellular ATP (10-100 μM) stimulated microglial secretion of a neurotrophic substance plasminogen, with a peak response at 5-10 min after the stimulation. This secretion was ATP-concentration dependent (Inoue et al., 1998).

neuroprotective phenotypes to neurotoxic ones.

under mild or severe hypoxia.

Neuroinflammation with activated microglia may play important roles in the pathogenesis of various neurodegenerative diseases including PD. Activation of microglia may be produced by some chemical signaling molecules released from the injured neurons such as dopaminergic neurons in the SN of the PD brain. Activated microglia may be neuroprotective, at least in the early phase, but may become neurotoxic later to contribute to the progression of the disease. Sawada M. et al. proposed a hypothesis of a toxic change in activated microglia from the neuroprotective phenotype to the neurotoxic one. Development of drugs to regulate activated microglia could be a promising approach for drug development for neurodegenerative diseases such as PD.
