Potent regulation of microglia-derived oxidative stress and dopaminergic neuron survival: substance P vs. dynorphin M. L. Block 1 , G. Li, L. Qin, X. Wu, Z. Pei, T. Wang, B. Wilson, J. Yang and J. S. Hong Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA 1 Correspondence: MD F1-01 NIEHS, P. O. Box 12233, Research Triangle Park, NC 27709, USA. E-mail: Block@niehs.nih.gov 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 3 H 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.—Block, M. L., Li, G., Qin, L., Wu, X., Pei, Z., Wang, T., Wilson, B., Yang, J., Hong, J. S. Potent regulation of microglia-derived oxidative stress and dopaminergic neuron survival: substance P vs. dynorphin. Key Words: microglia • oxidative stress • DA neurotoxicity • superoxide • NADPH oxidase • femtomolar
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Potent regulation of microglia-derived oxidative stress and dopaminergic neuron survival: substance P vs. dynorphin
Block, M. L.; Li, G.; Qin, L.; Wu, X.; Pei, Z.; Wang, T.; Wilson, B.; Yang, J.; Hong, J. S.
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, Volume 20 (2): 251
Fed of American Socs for Experimental Biology – Feb 1, 2006
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