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Physiological Concentration of Prostaglandin E2 Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway

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Abstract

This study investigated the physiological regulation of brain immune homeostasis in rat primary neuron-glial cultures by sub-nanomolar concentrations of prostaglandin E2 (PGE2). We demonstrated that 0.01 to 10 nM PGE2 protected dopaminergic neurons against LPS-induced neurotoxicity through a reduction of microglial release of pro-inflammatory factors in a dose-dependent manner. Mechanistically, neuroprotective effects elicited by PGE2 were mediated by the inhibition of microglial NOX2, a major superoxide-producing enzyme. This conclusion was supported by (1) the close relationship between inhibition of superoxide and PGE2-induced neuroprotective effects; (2) the mediation of PGE2-induced reduction of superoxide and neuroprotection via direct inhibition of the catalytic subunit of NOX2, gp91phox, rather than through the inhibition of conventional prostaglandin E2 receptors; and (3) abolishment of the neuroprotective effect of PGE2 in NOX2-deficient cultures. In summary, this study revealed a potential physiological role of PGE2 in maintaining brain immune homeostasis and protecting neurons via an EP receptor-independent mechanism.

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Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. We thank Drs. Jerry Liu, Hong Li, Peter Egeghy, and David Herr for the critical reading of the manuscript. We thank the animal care team members, Anthony Lockhart, Katrina Loper, and Johnny Green and the members of Fluorescence Microscopy and Imaging Center, Charles J. Tucker and Agnes Janoshazi. The US Environmental Protection Agency has provided administrative review and has approved this paper for publication. The views expressed in this paper are those of the authors and do not necessarily reflect the views of the US Environmental Protection Agency.

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Authors and Affiliations

  1. Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, NIEHS/NIH, 111 T.W. Alexander Dr., Research Triangle Park, NC, 27709, USA

    Shih-Heng Chen, Yueh-Feng Sung, Esteban A. Oyarzabal, Mingri Guo, Shuo Li, Qingshan Wang, Chun-Hsien Chu & Jau-Shyong Hong

  2. Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Yueh-Feng Sung

  3. U.S. Environmental Protection Agency, National Exposure Research Lab, Research Triangle Park, NC, USA

    Yu-Mei Tan

  4. Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA

    Jeremy Leonard

  5. Department of Laboratory Medicine, Tianjin Haihe Hospital/Haihe Clinical Institute of Tianjin Medical University, Tianjin, China

    Mingri Guo

  6. Department of Respiratory, Tianjin Medical University General Hospital, Tianjin, China

    Shuo Li

  7. Department of Neurology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Shiou-Lan Chen

  8. Institute of Behavioral Medicine, College of Medicine & Hospital, National Cheng Kung University, Tainan, Taiwan

    Ru-Band Lu

  9. Department of Psychiatry, National Cheng Kung University, Tainan, Taiwan

    Ru-Band Lu

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  1. Shih-Heng Chen
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Electronic Supplementary Material

Supplementary Figure 1

Xanthine/xanthine oxidase (X/XO)-generated superoxide was measured by the reduction of tetrazolium salt, WST-1. Briefly, assays were conducted in the presence of indicated concentrations of PGE2, 0.01 U xanthine oxidase, 50 μM xanthine, 250 μM partially acetylated WST-1 in 50 mM potassium phosphate buffer (pH 7.6) in a 96-well plate (100 μL/well final volume). Superoxide dismutase (SOD) served as a positive control. Xanthine was added to initiate the reaction, and absorbance at 450 nm was continuously monitored for 5 minutes using an SPECTAmax PLUS 384 spectrophotometer. Values are mean ± SEM from three independent experiments, with duplicates. ### P < 0.0001 Bonferroni’s t-test compared to X/XO plus WST-1 group. *** P < 0.0001 Bonferroni’s t-test compared to xanthine plus WST-1 group. (GIF 142 kb)

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Supplementary Figure 2

Rat primary microglia-enriched cultures were incubated with vehicle, 15 ng/ml of LPS, or indicated concentrations of PGE2 at 37 °C for 30 minutes. After incubation, the cells were lysed, and cAMP levels were determined using a cAMP assay kit. Data are expressed as picomoles cAMP per 1 million cells. Values are mean ± SEM from three independent experiments, with triplicates. *** P < 0.0001. (GIF 149 kb)

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Supplementary Figure 3

PGE2 and EP receptor agonists share pharmacophore features similar to conventional NOX2 inhibitors such as naloxone and apocynin. Results of the consensus pharmacophore analysis are illustrated by three-dimensional ball-and-stick relationships. The sticks represent the generic structure of 1) the prostaglandin; 2) NOX2 inhibitors (e.g., diphenyleneiodonium, apocynin, and naloxone); and 3) chemical agonists 17-phenyltrinor PGE2, butaprost, and CAY 10598, as ligands for the EP receptor(s). Structures of all molecules were superimposed in order to identify overlapping features. Annotation points for each of the three molecules were automatically detected and placed on relevant atoms and groups (e.g., donors, acceptors, aromatic centers, etc.) using the software Molecular Operating Environment (MOE), and these annotation points were converted into pharmacophore features with non-zero radii. Feature types for the balls include: hydrogen bond acceptor, blue; hydrogen bond acceptor/donor, light pink; hydrophobic centroid, green. The percentage represents how many chemicals share the same feature; and the score refers the radius of the feature. Atom centers must be within this radius to match the feature. The pharmacophore model was developed using ligand rather than crystal structures. (GIF 258 kb)

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Chen, SH., Sung, YF., Oyarzabal, E.A. et al. Physiological Concentration of Prostaglandin E2 Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway. Mol Neurobiol 55, 8001–8013 (2018). https://doi.org/10.1007/s12035-018-0965-4

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