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Potent regulation of microglia‐derived oxidative stress and dopaminergic neuron survival: substance P vs. dynorphin
Author(s) -
Block M. L.,
Li G.,
Qin L.,
Wu X.,
Pei Z.,
Wang T.,
Wilson B.,
Yang J.,
Hong J. S.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4553com
Subject(s) - microglia , nadph oxidase , substance p , neurotoxicity , oxidative stress , dynorphin , chemistry , neuron , substantia nigra , dynorphin a , dopaminergic , reactive oxygen species , neuropeptide , neuroglia , endocrinology , medicine , dopamine , biology , biochemistry , neuroscience , central nervous system , opioid peptide , inflammation , opioid , toxicity , receptor , organic chemistry
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. FASEB J. 20, 251–258 (2006)