Journal
FASEB JOURNAL
Volume 20, Issue 2, Pages 251-258Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.05-4553com
Keywords
microglia; oxidative stress; DA neurotoxicity; superoxide; NADPH oxidase; femtomolar
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Funding
- Intramural NIH HHS Funding Source: Medline
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Unregulated microglial activation has been implicated as a pivotal factor contributing to Parkinson's disease. Using mesencephalic neuron-glia cultures, we address the novel possibility that peptides endogenous to the substantia nigra (SN), substance P and dynorphin (10(-13)-10(-14) M), are opposing mediators of microglial activation and consequent DA neurotoxicity. Here, we identify that substance P (10-(13)-10(-14) M) is selectively toxic to DA neurons in a microglia-dependent manner. Mechanistically, substance P (10(-13)-10(-14) M) activated microglial NADPH oxidase to produce extracellular superoxide and intracellular reactive oxygen species (ROS). Neuron-glia cultures from mice lacking a functional NADPH oxidase complex (PHOX-/-) were insensitive to substance P (10(-13)-10(-14) M) -induced loss of DA neuron function. Mixed glia cultures from (PHOX-/-) mice failed to show a significant increase in intracellular ROS in response to substance P compared with control cultures (PHOX-/-). Further, dynorphin (10(-14) M) inhibited substance P (10(-13) M) -induced loss of [H-3] DA uptake. Here we demonstrate a tightly regulated mechanism governing microglia-derived oxidative stress, where the neuropeptide balance of dynorphin and substance P is critical to DA neuron survival.
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