51. Genistein attenuates retinal inflammation associated with diabetes by targeting of microglial activation.
- Author
-
Ibrahim AS, El-Shishtawy MM, Peña A Jr, and Liou GI
- Subjects
- Animals, Anti-Inflammatory Agents administration & dosage, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Diabetes Mellitus, Experimental, Diabetic Retinopathy pathology, Enzyme Activation drug effects, Extracellular Signal-Regulated MAP Kinases, Genistein administration & dosage, Glycation End Products, Advanced, Inflammation complications, Inflammation pathology, Intravitreal Injections, Male, Microglia enzymology, Microglia metabolism, Microglia pathology, Phosphorylation drug effects, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Rats, Rats, Sprague-Dawley, Retina drug effects, Serum Albumin metabolism, Tumor Necrosis Factor-alpha metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Glycated Serum Albumin, Diabetic Retinopathy complications, Diabetic Retinopathy drug therapy, Genistein pharmacology, Genistein therapeutic use, Inflammation drug therapy, Microglia drug effects, Retina pathology
- Abstract
Purpose: Diabetic retinopathy (DR) is associated with microglial activation and increased levels of inflammatory cytokines. Genistein, a tyrosine kinase inhibitor, has been shown to possess anti-inflammatory potential that so far untested in animal models of diabetes. The aims of this study are to evaluate the efficacy of genistein for alleviation of diabetes-induced retinal inflammation and also to gain insight into the molecular mechanisms involved therein by analyzing the effect of genistein on concomitant microglia activation in the diabetic retina and in isolated cells., Methods: Streptozotocin (STZ)-induced diabetic Sprague Dawley rats were used. After diabetes was established for two weeks a single intravitreal injection of genistein or vehicle was performed. Forty-eight hours later, rats were killed, their retinal and vitreal samples were processed for Quantitative Real Time-PCR (qRT-PCR) and Enzyme-linked immunosorbent assay (ELISA) analyses, respectively. For the in vitro study, isolated microglial cells from retinas of newborn rats were used., Results: mRNA as well as protein levels for tumor necrosis factor α (TNF-α), a robust marker of inflammation, were increased in the retina early in the course of diabetes. Moreover, diabetes resulted in elevation of ionized calcium binding adaptor molecule-1 (Iba1) mRNA, known to be upregulated in activated microglia. These effects of diabetes in retina were all reduced by intervention treatment with genistein. Using an in vitro bioassay, we demonstrated the release of TNF-α from microglia activated by glycated albumin, a risk factor for diabetic disorders. This inflammatory signal involves the activation of tyrosine kinase and its subsequent events, ERK and P38 MAPKs. Genistein represses the release of TNF-α and significantly inhibits ERK and P38 phosphorylation in activated microglial cells by acting as a tyrosine kinase inhibitor., Conclusions: These findings show genistein to be effective in dampening diabetes-induced retinal inflammation by interfering with inflammatory signaling (ERK and P38 MAPKs) that occurs in activated microglia. This beneficial effect of genistein may represent a new intervention therapy to modulate early pathological pathways long before the occurrence of vision loss among diabetics.
- Published
- 2010