Potent Regulation of Microglia-derived Oxidative Stress and Dopaminergic Neuron Survival: Substance P Vs. Dynorphin.
From: Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. Block@niehs.nih.gov
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publish Date: Feb 2006
- ISSN: 1530-6860
- Volume: 20
- Issue: 2
- Pages: 251-8
- Medium: Internet
- Language: English
- Citation (JAMA): Block M L, Li G, Qin L, et al. Potent Regulation of Microglia-derived Oxidative Stress and Dopaminergic Neuron Survival: Substance P Vs. Dynorphin.. FASEB J. Feb 2006;20:251-8
Abstract
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 [3H] 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.
Mesh Headings (Keywords): Animals, Cell Survival, Cells, Cultured, Dopamine, Dose-Response Relationship, Drug, Dynorphins, Female, Gene Deletion, Male, Mice, Microglia, NADPH Oxidase, Neurons, Oxidative Stress, Rats, Reactive Oxygen Species, Substance P
Check for Full Text / PubMed Unique Identifier (PMID): 16449797
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