Authors: S Cellek W Qu A M Schmidt S Moncada
Publish Date: 2003/12/16
Volume: 47, Issue: 2, Pages: 331-339
Abstract
We have previously shown that in diabetes nitrergic neurones innervating the urogenital and gastrointestinal organs undergo a selective degenerative process This comprises an initial insulinreversible decrease in neuronal nitric oxide synthase nNOS in the axons followed by apoptosis of the nitrergic neurones a process that is not reversible by insulin Since apoptosis was independent of serum glucose concentrations and advanced glycation endproducts AGEs have been implicated in the pathogenesis of diabetic complications we have now measured AGEs in the serum and penis pyloric sphincter and pelvic ganglia of diabetic animals at different times after streptozotocin treatment Furthermore we have studied their effect in vitro on human neuroblastoma SHSY5Y cells in the presence or absence of nNOS expressionSerum AGEs were measured using fluorometry and ELISA Accumulation of AGEs in the tissues was evaluated with immunohistochemistry The viability apoptosis and oxidative stress in SHSY5Y cells were measured upon exposure to AGEs or high concentrations of glucoseAGEs increased gradually in the serum and tissues of streptozotocininduced diabetic rats this process was not affected by delayed insulin treatment In SHSY5Y cells AGEs but not high glucose concentrations increased the reactive oxygen species and caspase3dependent apoptosis in a synergistic fashion with endogenous nitric oxide NO Apoptosis was prevented by treatment with a NOS inhibitor a pancaspase inhibitor a soluble receptor of AGEs or an antioxidant but not an inhibitor of soluble guanylate cyclase
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