The anti-inflammatory effect of omega-3 polyunsaturated fatty acids dramatically decreases by iron in the hippocampus of diabetic rats

Aims: Receptor for advanced glycation end products (RAGE) production is induced by diabetes. Microglial cells are activated by RAGE and produce inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and oxidative stress markers. Persistent production of TNF-alpha can provide a link between diabetes and Alzheimer's disease (AD). The purpose of this study was to investigate the effect of concomitant use of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) with iron supplements on microglial cell activation and inflammatory conditions in the hippocampus of type 2 diabetic rats. Main methods: Diabetic and normal Wistar rats were divided into six groups. Oxidative stress markers (total oxidant status (TOS), total antioxidant capacity (TAC), and malondialdehyde (MDA)), mRNA expression and protein levels of RAGE and TNF-alpha were evaluated in the hippocampus of the controls and supplemented with ferrous sulfate and omega-3 PUFAs alone and together rats. Also, the entry of microglia cells into the hippocampus was evaluated by immunohistochemistry technique. Key findings: Levels of the microglial activation (2.4 fold, p < 0.0001), MDA (84%, p < 0.0001) and oxidative stress index (OSI) (11%, p = 0.0094), mRNA expression and protein contents of RAGE (1.83 fold and 82% respectively) and TNF-alpha (2.25 fold and 86% respectively) were strongly influenced by negative effect of iron compared to the group receiving only omega-3 PUFAs which was dramatically improved by vitamin E. Significance: These observations indicated that the co-supplementation of ferrous sulfate with omega-3 PUFAs decreases the anti-inflammatory ability of omega-3 PUFAs in the hippocampus of diabetic rats via RAGE/TNF-alpha-induced oxidative stress pathway up-regulation.