Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

Abstract

Aims/hypothesis. We have previously shown that in diabetes nitrergic neurones innervating the urogenital and gastrointestinal organs undergo a selective degenerative process. This comprises an initial insulin-reversible 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 (SH-SY5Y) cells in the presence or absence of nNOS expression. Methods. Serum AGEs were measured using fluorometry and ELISA. Accumulation of AGEs in the tissues was evaluated with immunohistochemistry. The viability, apoptosis and oxidative stress in SH-SY5Y cells were measured upon exposure to AGEs or high concentrations of glucose. Results. AGEs increased gradually in the serum and tissues of streptozotocin-induced diabetic rats; this process was not affected by delayed insulin treatment. In SH-SY5Y cells, AGEs, but not high glucose concentrations, increased the reactive oxygen species and caspase-3-dependent apoptosis in a synergistic fashion with endogenous nitric oxide (NO). Apoptosis was prevented by treatment with a NOS inhibitor, a pan-caspase inhibitor, a soluble receptor of AGEs or an anti-oxidant, but not an inhibitor of soluble guanylate cyclase. Conclusions/interpretation. The synergistic actions of NO and AGEs account for the irreversible nitrergic degeneration in diabetes. [Diabetologia (2004) 47: 331-339]

Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: analysis of data from tadalafil clinical trials

“…Furthermore, endothelial function is impaired in the presence of hyperglycaemia, primarily through a decrease in NO bioavailability and responsiveness [23]. In addition, hyperglycaemia may produce reactive oxygen species, cause apoptosis of the nitrergic nerves, or produce smooth muscle fibrosis, further damaging the NO-cGMP erectile function pathway [24,25].…”

Endothelial dysfunction in diabetic erectile dysfunction

“…79 The importance of AGEs in diabetic ED was first described by Seftel et al 80 AGEs impair both the neuronal and endothelial production of NO and cause cavernosal tissue and nerve fiber damage via membrane lipid peroxidation. 80,81 AGEs accumulate in the collagen of the diabetic tunica and diabetic cavernosal tissue in men, in particular, endothelial and smooth muscle cells. [80][81][82][83][84] One of the receptors for AGEs, galectin-3, is also increased in the diabetic rat penis.…”

“…80,81 AGEs accumulate in the collagen of the diabetic tunica and diabetic cavernosal tissue in men, in particular, endothelial and smooth muscle cells. [80][81][82][83][84] One of the receptors for AGEs, galectin-3, is also increased in the diabetic rat penis. 82 Inhibition of AGEs formation by aminoguanidine improves erectile response.…”

Therapeutic effect of combination of alagebrium (ALT-711) and sildenafil on erectile function in diabetic rats

“…Recently, it has been reported by Cellek and Usta that at least a 6 --8-weeks diabetes period is required to observe any irreversible neural degeneration in penile tissue. 6,27,28 Hence, to assess the protective effect of any treatment option, the ideal way is to start the mentioned ED treatment options at least after a 6 --8-weeks diabetes period. We should express that as the STZ diabetes model used in the present study is a typical type-1 diabetes model, it is very difficult to keep the animals alive for such a long time period (6--8 weeks for diabetes and an additional 6--8 weeks for treatment).…”