Synergism in the repression of COX-2- and TNFalpha-induction in platelet activating factor-stressed human neural cells.
Platelet activating factor (PAF; beta-acetyl-gamma-O-hexadecyl-l-alpha-phosphatidylcholine) triggers a rapid pro-inflammatory gene expression program in primary cultures of human neural (HN) cells. Two genes and gene products consistently induced after PAF treatment are the cytosoluble prostaglandin synthase cycloooxygenase-2 (COX-2) and the pro-apoptotic tumor necrosis factor alpha (TNFalpha). Both of these mediators are associated with the activation of inflammatory signaling, neural cell dysfunction, apoptosis and brain cell death, and both have been found to be up-regulated after brain injury in vivo. In this study we investigated the effects of the non-halogenated synthetic glucocorticoid budesonide epimer R (BUDeR), the novel PAF antagonist LAU-0901, and the electron spin trap and free radical scavenger phenyl butyl nitrone (PBN), upon early COX-2 and TNFalpha gene activation and prostaglandin E(2) (PGE(2)) release in PAF-stressed primary HN cells. The data indicate that these three biochemically unrelated classes of inflammatory repressors act synergistically in modulating PAF-induced up-regulation of COX-2, TNFalpha, and PGE(2) by quenching oxidative stress or inflammatory signaling, resulting in increased HN cell survival. These, or analogous classes of compounds, may be useful in the design of more effective combinatorial pharmacotherapeutic strategies in the treatment of complex neuro-inflammatory disorders.
Boetkjaer
Anja
A
The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK 2100 Copenhagen, Denmark.
Boedker
Merete
M
Cui
Jian-Guo
JG
Zhao
Yuhai
Y
Lukiw
Walter J
WJ
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D019819:Budesonide / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004357:Drug Synergism; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010972:Platelet Activating Factor / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000378:metabolism* / Q000503:physiopathology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000893:Anti-Inflammatory Agents; D003497:Cyclic N-Oxides; D004095:Dihydropyridines; C487837:LAU 0901; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; C029217:phenyl-N-tert-butylnitrone; D019819:Budesonide; D051546:Cyclooxygenase 2; D015232:Dinoprostone