Elucidation of multiple actions of reactive nitrogen species in degeneration of midbrain dopaminergic neurons

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With special reference to the actions of reactive nitrogen species and related compounds, this study addressed the roles of oxidative stress in induction of selective degeneration of midbrain nigral dopaminergic neurons, a hallmark of Parkinson disease pathology. (1) Activation of microgia in midbrain slice cultures by lipopolysaccharide induced degeneration of dopaminergic neurons, which was mediated by increases in expression of inducible nitric oxide (NO) synthase and production of NO. Dismutation of superoxide did not inhibit induction of neuronal death, whereas a JNK inhibitor and α-tocopherol protected dopaminerguc neurons without affecting NO production. On the other hand, degeneration of dopaminergic neurons induced by application of thrombin to midbrain slice cultures was associated with activation of multiple MAP kinase family members and a subsequent increase in expression of NO synthase. Inhibition of these enzymes as well as depletion of microglia markedly suppressed dopaminergic neurodegeneration. Thus, thrombin was suggested to exert selective dopaminergic neurotoxicity via microglial activation and increased NO production. (2) 3-Nitrotyrosine (3-NT), which is formed by reaction of tyrosine with NO-related molecular species, induced degeneration of midbrain dopaminergic neurons in culture. Cellular uptake of 3-NT via amino acid transporters was essential for induction of cell death, and 3-NT promoted superoxide production in cells, suggesting that 3-NT promotes degeneration of dopaminergic neurons by acting as an intracellular superoxide generator. (3) Knockdown of DJ-1, a protein encoded by a gene responsible for familial Parkinson disease, rendered SH-SY5Y cells vulnerable to several agents including 6-OHDA, H_2O_2 and an NO donor. In addition, treatment of SH-SY5Y cells and C6 cells with H_2O_2 increased expression of DJ-1, suggesting that DJ-1 functions as a part of endogenous protective mechanisms against oxidative stress.