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Ping Hu, Jeffery S Thinschmidt, Sergio Caballero, Robert Baxter, Louise Cole, Samuel Adamson, Tailoi Chan-Ling, Maria Grant; Loss of Survival Factors and Activation of Inflammatory Cascades in the Autonomic Centers of the Brain: Implications for the Pathogenesis of Diabetic Retinopathy (DR). Invest. Ophthalmol. Vis. Sci. 2014;55(13):2255.
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© ARVO (1962-2015); The Authors (2016-present)
Complex bidirectional interactions between cells of the immune and nervous systems contribute additional regulatory mechanisms that influence the cellular activities of both systems. We asked if this immune-CNS interaction may influence the pathogenesis of DR. To address this question, we investigated the roles of key neuronal and immune modulators.
STZ-induced T1D mice, age-matched controls, and T1D mice treated with minocycline (an agent that has marked anti-inflammatory activity that crosses the BBB/BRB and has been used to treat diabetic retinopathy) and 6 diabetic & 6 age-matched control human eyes were used. Neuronal, astrocytic and microglial changes were examined with multiple marker immunohistochemistry using antibodies against insulin-like Growth Factor (IGF) -1, insulin-like growth factor-binding protein (IGFBP)-3, MMP2, Iba-1 (for detection of activated microglia) and CD39 (ecto-ADPase -a regulator of the purinergic system which plays a role in preventing inflammation).
In the diabetic hypothalamus (HYPO), neuronal soma diameter was reduced by 20% (p<0.05) whilst neuronal expression of IGFBP-3 and IGF-1 was reduced by 32% (p<0.05) and 15% (p<0.05) respectively. Markers associated with inflammation, MMP2 and Iba-1 were up regulated in astrocytes (46%, p<0.01) and microglia (29%, p<0.05). The expression of CD39 was down-regulated by 27%, p<0.05) on the microglia and blood vessels. Consistent with the changes in diabetic HYPO, CD39+ cell density was reduced by 18% (p<0.05), while Iba-1+ microglial density increased by 29% (p<0.05) in the diabetic mouse retina. In human diabetic retina, CD39 expression on microglia and blood vessels was reduced by 35% (p<0.05), while Iba-1+ cell density increased by 24% (p<0.05). The increased Iba-1 and MMP2 and reduced CD39 expression observed in the diabetic HYPO, as well as the increased Iba-1+ microglia in diabetic retina could be mitigated by treatment with minocycline.
Taken together, our data leads us to suggest that loss of the neuronal survival factors IGFBP-3 and IGF-1 result in neuronal loss and shrinkage in HYPO and are accompanied by activation of inflammatory factors such as Iba-1 and MMP-2. Agents that target both brain and retinal inflammation may be more effective in the treatment of DR than agents that only influence the retina.
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