Anti‐inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia

Abstract

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.

Ginkgo biloba, a free oxygen radical scavenger, affects inflammatory mediators to diminish the occurrence of experimental myringosclerosis

“…Ginkgo biloba also exerts an antiphlogistic effect on inflammatory cells, mostly by suppressing the production of active oxygen and nitrogen species [8]. Furthermore, the flavone component of GBE also inhibits lipid peroxidation reactions and platelet aggregation [15] and enhances antioxidant enzyme activities [20]. The free radical scavenging activity of GBE is comparable to that of other known antioxidants such as vitamins A and C, as well as the tripeptide glutathione peroxidase [15].…”

“…Ascorbic acid and superoxide dismutase acting as scavengers of superoxide radicals indirectly preserve activity of NO. GBE can scavenge NO and inhibit its production by NO synthase, reducing the nitrate levels in a dose-dependent manner [15]. In some studies it was found that NO levels increased in untreated rats after myringotomy [1].…”

Plant‐derived polyphenols attenuate lipopolysaccharide‐induced nitric oxide and tumour necrosis factor production in murine microglia and macrophages

“…iNOS, IL1ß, IL6 and TNF have been detected in amyloid plaques and adjacent microglial and astroglial cells [59]. Activated glia are a further source of ROS (such as superoxide and NO) through the activation of NADPH oxidase and iNOS, respectively [60,61]. ROS act as second messengers in proinflammatory signal transduction and intracellular acting antioxidants such as flavonoids including apigenin and diosmetin can thus act as anti-inflammatory drugs for these diseases.…”

The Thiol Antioxidant Lipoic Acid and Alzheimer’s Disease

“…Ras interacts with PI3-kinase, protein kinase C, diacylglycerol kinase, and MAP-kinase-kinase-kinase, regulating expression of IL-1 b, IL-6, and iNOS. LA can scavenge intracellular free radicals (acting as second messengers), downregulate proinflammatory redox-sensitive signal transduction processes including NF-kB translocation, and thus attenuate the release of more free radicals and cytotoxic cytokines (Bierhaus et al 1997;Wong et al 2001a).…”