الفهرس 
Diabestes MillitusOnly 14 pages are availabe for public view
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Abstract
Diabetes is a major threat to global public that is associated with many complications threatening life. Diabetic retinopathy (DR) is the most feared complication of diabetes that is a leading cause of adult vision loss and blindness. As a result, DR is becoming an increasing burden to society that needs improved and preventive therapies. These therapies could be discovered by unraveling the pathophysiology of DR which in itself, presents quite a unique challenge. Recently, retinal microglia, a subtype of glial-immune sentinel cells pre-stationed in the tissue, are blamed for the progression of DR due to their release of soluble cytotoxins that contribute to neuronal and vascular cell death seen in DR. However, the underlying mechanism of microglial activation during diabetes is still incompletely understood. Therefore, the overall goals of this study are 1) to elucidate the mechanism(s) through which the retinal microglia release neuron-vascular toxic factors in response to hyperglycemia in one hand, 2) and on other hand is to target microglia activation by using some natural phenolic compounds with high safety profile to dampen diabetes-induced inflammation.To achieve the first goal, microglia activation was characterized in streptozotocin (STZ)-injected rats and in isolated microglial cells. The results showed that in 8-weeks diabetic retina, Amadori-glycated Albumin (AGA)-like epitopes were featured in the regions of microglia distribution, implicating a pathogenic effect on microglial activation. To test this, diabetic rats were treated intravitreally with A717, a specific AGA neutralizing antibody, or murine IgG. Relative to nondiabetics, diabetic rats (IgG-treated) manifested 3.9 and 7.9-fold increases in Iba-1, ionized calcium binding adaptor molecule-1 known to be upregulated in activated microglia, and TNF-α mRNAs, respectively. Treatment of diabetic rats with A717 significantly attenuated over-expression of these mRNAs. Guided by these results, a cultured retinal microglia model was developed to study microglial response after AGA treatment and the mechanistic basis behind this response in more details. The results showed that increased ROS formation and tyrosine phosphorylation with subsequent activation of ERK and P38, but not JNK, are molecular events underpinning retinal microglial TNF-α release during AGA-treatment. In light of these findings, the second goal was then to dampen microglia activation during diabetes using natural phenolic compounds. The rational approach would rely on the selection of anti-oxidant and/or tyrosine kinase inhibitors from this broad category of compounds. The most likely candidates are Cannabidiol (CBD), as an antioxidant, and genistein, as a tyrosine kinase inhibitor because they both have wide therapeutic indices with very low toxicity and their efficacy has been demonstrated in different animal models of inflammatory diseases. To accomplish the second goal, STZ-induced diabetic rats were used. After diabetes was established for two weeks a single intravitreal injection of CBD, genistein or vehicle was performed. The results showed that mRNA as well as protein levels for TNF-α, a robust marker of inflammation, were increased in the retina early in the course of diabetes. Moreover, diabetes resulted in elevation of Iba1 mRNA. These effects of diabetes in retina were all reduced by intervention treatment with CBD or genistein. In conclusion, it is believed that CBD or genistein, by interfering with inflammatory signaling (ROS, tyrosine kinase, ERK and P38 MAPKs) that occurs in activated microglia, may represent a potentially new therapeutic approach to modulate early pathological pathways long before the occurrence of vision loss among diabetics.