Anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia.
Advanced glycation endproducts (AGEs) accumulate on long-lived protein deposits including beta-amyloid plaques in Alzheimer's disease (AD). AGE-modified amyloid deposits contain oxidized and nitrated proteins as markers of a chronic neuroinflammatory condition and are surrounded by activated microglial and astroglial cells. We show in this study that AGEs increase nitric oxide production by induction of the inducible nitric oxide synthase (iNOS) on the mRNA and protein level in the murine microglial cell line N-11. Membrane permeable antioxidants including oestrogen derivatives (e.g. 17beta-oestradiol) thiol antioxidants (e.g. (R+)-alpha-lipoic acid) and Gingko biloba extract EGb 761, but not phosphodiesterase inhibitors such as propentophylline, prevent the up-regulation of AGE-induced iNOS expression and NO production. These results indicate that oxygen free radicals serve as second messengers in AGE-induced pro-inflammatory signal transduction pathways. As this pharmacological mechanism is not only relevant for Alzheimer's disease, but also for many chronic inflammatory conditions, such membrane-permeable antioxidants could be regarded not only as antioxidant, but also as potent therapeutic anti-inflammatory drugs.
Wong
A
A
Neuroimmunological Cell Biology, IZKF Leipzig, Johannisallee 30a, 04103 Leipzig, Germany.
Dukic-Stefanovic
S
S
Gasic-Milenkovic
J
J
Schinzel
R
R
Wiesinger
H
H
Riederer
P
P
Münch
G
G
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D005609:Free Radicals / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D058225:Plaque, Amyloid / Q000187:drug effects / Q000378:metabolism; D020033:Protein Isoforms / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000975:Antioxidants; D005609:Free Radicals; D017127:Glycation End Products, Advanced; D020033:Protein Isoforms; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase