The breakdown of preformed advanced glycation end products reverses erectile dysfunction in streptozotocin-induced diabetic rats: preventive versus curative treatment.
OBJECTIVE
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.


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.
Department of Urology, Section of Andrology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Mustafa F
MF
Usta
Muammer
M
Kendirci
Serap
S
Gur
Neale A
NA
Foxwell
Trinity J
TJ
Bivalacqua
Selim
S
Cellek
Wayne J G
WJ
Hellstrom
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003925:Diabetic Angiopathies / Q000139:chemically induced / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006146:Guanidines / Q000008:administration & dosage*; D007150:Immunohistochemistry; D018783:Impotence, Vasculogenic / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013844:Thiazoles / Q000008:administration & dosage*
D017127:Glycation End Products, Advanced; D006146:Guanidines; D013844:Thiazoles; D013311:Streptozocin; C406794:alagebrium; C004479:pimagedine