TY - JOUR
T1 - The breakdown of preformed advanced glycation end products reverses erectile dysfunction in streptozotocin-induced diabetic rats
T2 - Preventive versus curative treatment
AU - Usta, Mustafa F.
AU - Kendirci, Muammer
AU - Gur, Serap
AU - Foxwell, Neale A.
AU - Bivalacqua, Trinity J.
AU - Cellek, Selim
AU - Hellstrom, Wayne J.G.
N1 - Funding Information:
ALT‐711 was kindly provided by Alteon Inc., Parsippany, NJ, USA. This study was funded by the Juvenile Diabetes Research Foundation (S.C.), a scholarship from the Sexual Medicine Society of North America, Bayer/GlaxoSmithKline (M.F.U.), the American Medical Association (T.J.B.), and Young Investigator Award from the International Society for Sexual and Impotence Research (T.J.B.). The authors thank Dr. Kemal H. Gülkesen for assistance in statistical analyses.
PY - 2006/3
Y1 - 2006/3
N2 - Objectives. Accumulation of advanced glycation end products (AGEs) has been linked to many of the complications of diabetes mellitus, including erectile dysfunction (ED). Furthermore, it has been demonstrated that inhibitors of AGE formation, such as aminoguanidine, can prevent ED in diabetic animals. However, it is unknown whether late administration of a putative cross-link breaker, ALT-711, can reverse diabetic ED. We therefore compared ALT-711 and aminoguanidine in their ability to reverse ED in diabetic rats. Materials and methods. Male Sprague-Dawley rats were randomly divided into four groups: (i) age-matched controls; (ii) streptozotocin (STZ)-induced diabetic rats (60 mg/kg; intraperitoneal injection); (iii) STZ diabetic rats treated with ALT-711 (3 mg/kg/day, intraperitoneal injection); and (iv) STZ diabetic rats treated with aminoguanidine (1 gm/ L in drinking water) during the final 6 weeks of 12 weeks of induced diabetes. At the end of 12 weeks, erectile response to cavernous nerve stimulation (CNS) was determined. Neuronal nitric oxide synthase (nNOS) contents were measured in all penises, and AGE levels were determined both in penile tissues and in serum samples. Results. Erectile responses to CNS and penile nNOS protein content were significantly reduced, while AGE levels were elevated in the penises and serum of untreated diabetic animals. Treatment with ALT-711, but not with aminoguanidine, reversed ED and nNOS depletion and reduced serum and penile tissue AGE levels. Conclusions. These results suggest that cross-link breakers, such as ALT-711, are the optimal therapeutic approach, compared with treatment with inhibitors of AGE formation, in the reversal of diabetes-related ED.
AB - Objectives. Accumulation of advanced glycation end products (AGEs) has been linked to many of the complications of diabetes mellitus, including erectile dysfunction (ED). Furthermore, it has been demonstrated that inhibitors of AGE formation, such as aminoguanidine, can prevent ED in diabetic animals. However, it is unknown whether late administration of a putative cross-link breaker, ALT-711, can reverse diabetic ED. We therefore compared ALT-711 and aminoguanidine in their ability to reverse ED in diabetic rats. Materials and methods. Male Sprague-Dawley rats were randomly divided into four groups: (i) age-matched controls; (ii) streptozotocin (STZ)-induced diabetic rats (60 mg/kg; intraperitoneal injection); (iii) STZ diabetic rats treated with ALT-711 (3 mg/kg/day, intraperitoneal injection); and (iv) STZ diabetic rats treated with aminoguanidine (1 gm/ L in drinking water) during the final 6 weeks of 12 weeks of induced diabetes. At the end of 12 weeks, erectile response to cavernous nerve stimulation (CNS) was determined. Neuronal nitric oxide synthase (nNOS) contents were measured in all penises, and AGE levels were determined both in penile tissues and in serum samples. Results. Erectile responses to CNS and penile nNOS protein content were significantly reduced, while AGE levels were elevated in the penises and serum of untreated diabetic animals. Treatment with ALT-711, but not with aminoguanidine, reversed ED and nNOS depletion and reduced serum and penile tissue AGE levels. Conclusions. These results suggest that cross-link breakers, such as ALT-711, are the optimal therapeutic approach, compared with treatment with inhibitors of AGE formation, in the reversal of diabetes-related ED.
KW - ALT-711
KW - Advanced glycation end products
KW - Cross-link breaker
KW - Diabetes
KW - Diabetic complications
KW - Erectile dysfunction
KW - Nitrergic
KW - Nitric oxide
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U2 - 10.1111/j.1743-6109.2006.00217.x
DO - 10.1111/j.1743-6109.2006.00217.x
M3 - Article
C2 - 16490017
AN - SCOPUS:33645968445
SN - 1743-6095
VL - 3
SP - 242
EP - 252
JO - Journal of Sexual Medicine
JF - Journal of Sexual Medicine
IS - 2
ER -