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Mustafa F. Usta (1,2) , Muammer Kendirci (2) , Trinity J Bivalacqua (2) ,

DELAYED ADMINISTRATION OF ALT-711, BUT NOT OF AMINOGUANIDINE IMPROVES ERECTILE FUNCTION IN STREPTOZOTOCIN DIABETIC RATS: CURATIVE VERSUS PREVENTIVE MEDICINE. Mustafa F. Usta (1,2) , Muammer Kendirci (2) , Trinity J Bivalacqua (2) ,

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Mustafa F. Usta (1,2) , Muammer Kendirci (2) , Trinity J Bivalacqua (2) ,

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  1. DELAYED ADMINISTRATION OF ALT-711, BUT NOT OF AMINOGUANIDINE IMPROVES ERECTILE FUNCTION IN STREPTOZOTOCIN DIABETIC RATS: CURATIVE VERSUS PREVENTIVE MEDICINE Mustafa F. Usta (1,2), Muammer Kendirci (2), Trinity J Bivalacqua (2), Serap Gur (2), Neale A Foxwell (3), Wayne J.G. Hellstrom (2) , Selim Cellek (3) Akdeniz University School of Medicine Department of Urology, Section of Andrology Antalya-TURKEY (1) Tulane University, School of Medicine Department of Urology, Section of AndrologyNew Orleans, LA-USA (2) Wolfson Institute for Biomedical Research University College, London-UK (3)

  2. Common Conditions Associated with Erectile Dysfunction Vascular Disease 30% Diabetes 40% Multiple Sclerosis 3% Endocrine Disorders 6% Radical Surgery 13% Spinal Cord Injury 8% Zonszein. Urol Clin North Am. 1995

  3. Diabetes and Erectile Dysfunction *Diabetes affects >15 million individuals in the USA, and prevalence of ED reported to be as high as 50 - 75%. *Causative factors in diabetic ED are the reduction in NOS nerve fibers, disordered endothelial smooth muscle relaxation, and NO bio-availability. *Animal models of diabetes exhibit ED with significant decreases in eNOS & nNOS protein and NOS-containing nerve fibers in the dorsal and intracavernosal nerves. El Sakka AI et al., IJIR 1999 Vernet D et al., Endocrinology 1995 Akingba A & Burnett AL, Mol Urol 2001 Bivalacqua TJ et al., BBRC 2001

  4. Advanced Glycation End Products (AGE) and ED *Possible relation between elevated levels of AGE in DM and ED *AGEs are responsible for the impairment of NO-mediated corpus cavernosal smooth muscle relaxation in DM *The protective effect of Aminoguanidine (selective AGE inhibitor) on erectile function in diabetic rats Seftel A et al, Urology, 1997 Cartledge JJ et al, BJU Int, 2001 Usta et al, J Urol, 2003 Usta et al, BJU Int 2004

  5. What is AGE? *The result of nonenzymatic glycation of proteins commonly encountered in systemic disease (DM, CRF and ageing) *The reaction occurs between reduced sugars (aldoses and ketoses) and free amino groups of proteins (Amodori product, Maillard reaction) *One of the most important primer target for Maillard reaction are long lived proteins such:COLLAGEN, LAMININ *AGEs decrease eNOS expression in the vascular endothelium, causing to decreased NO production *After inducing diabetes in rats AGEs occur over a period of weeks (3-5 weeks) Singh R et al, Diabetologia 2001 Vlasara H, Diabetes Metab Res Rev 2001 Cellek S et al, Diabetes 2003

  6. Diabetes mellitus Axonal transport defect Oxidative stress AGEs accumulation NO Mitochondrial dysfunction Caspase-3 activation POINT OF NO RETURN nNOS depletion in the axons Apoptotic cell death Nitrergic degeneration Nitrergic dysfunction serum AGEs Reversible phase Irreversible phase Cellek S et al., Diabetes 2003

  7. SPECIFIC AIMS 1. Accumulation of AGEs has been linked to diabetes related ED. Inhibitors of AGEs such as AMG prevents ED in diabetic rats ( If administered immediately). We assessed the effect of late administered AMG on erectile function in diabetic rats. 2. Additionally, we investigated whether late administration of a cross-link breaker ALT-711 (alagebrium) can protect against the development of ED in a diabetic rat model.

  8. STUDY DESIGN Harlan Sprague-Dawley rats (18 to 20 weeks old) were divided into 4 groups: Group-1: Control (n=10) Group-2:STZ-diabetic rats (n=10) (Free access to water and standard diet) Group-3: STZ-diabetic rats treated with ALT-711 (3mg/kg i.p. daily)* (n=12) Group-4: STZ-diabetic rats treated with AMG (AMG added to drinking water 1g/l per day)* (n=11) *ALT and AMG treatment started 6 weeks after DM induction

  9. STUDY PROTOCOL *Blood glucose level was assessed every two weeks throughout the study period (10mmol/l) * Assessment of erection:Three months after induction of diabetes an in vivo erectile protocol(Intracavernosal pressure and total ICP measurements in response to cavernosal nerve stimulation) was employed *AGE (serum):ELISA and fluorometry AGE ( penis): Immunofluorescence nNOS (penis): Western Blotting

  10. RESULTS-1

  11. RESULTS-2

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  13. RESULTS-4

  14. RESULTS-5

  15. RESULTS-6

  16. CONCLUSIONS * STZ induced diabetes caused ED in rats within 12 weeks. However ALT-711 treatment for the last 6 weeks improved erectile function in diabetic rats which was comparable to non-diabetic control group * Treatment with AMG for the 6 weeks did not reverse erectile function * ALT-711 treatment normalized the nNOS levels suggesting that AGEs might be interfering with the axonal transport of nNOS. Therefore our results may also suggest a new mechanism by which AGEs may have a detrimental effect on NO production in the autonomic nervous system *The effect of ALT-711 on arterial compliance has been assessed in a human study. The results of that study clearly demonstrated that ALT-711 improved total arterial compliance in aged humans with vascular stiffness. ALT-711 may provide a novel therapeutic approach in endothelial dysfunction as well as ED, which are commonly seen with diabetes.

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