Accepted Manuscript Correspondence Pioglitazone prevents cavernosal nerve injury after radical prostatectomy Louis A. Aliperti, Wayne J.G. Hellstrom PII: DOI: Reference:

S0306-9877(14)00033-4 http://dx.doi.org/10.1016/j.mehy.2014.01.022 YMEHY 7485

To appear in:

Medical Hypotheses

Received Date: Accepted Date:

24 July 2013 22 January 2014

Please cite this article as: L.A. Aliperti, W.J.G. Hellstrom, Pioglitazone prevents cavernosal nerve injury after radical prostatectomy, Medical Hypotheses (2014), doi: http://dx.doi.org/10.1016/j.mehy.2014.01.022

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Pioglitazone prevents cavernosal nerve injury after radical prostatectomy

Louis A. Aliperti*; Wayne J. G. Hellstrom, MD, FACS* *Tulane University Medical Center, Department of Urology, New Orleans, Louisiana

Summary Word Count: 63 Manuscript Word Count: 590

Corresponding Author: Wayne J. G. Hellstrom MD, FACS Tulane University, Health Sciences Center Department of Urology, 1430 Tulane Avenue, SL-42 New Orleans, LA 70112 Phone: (504) 988-3361 Fax: (504) 988-5059 E-mail: [email protected]

Dear Sir or Madam: The incidence of some degree of erectile dysfunction (ED) after radical prostatectomy (RP) is estimated to approach 60-89%. Neuropraxia of the cavernosal nerves is a recognized etiology for post prostatectomy ED, after surgery through traction, thermal injury, ischemia, or inflammation. Neurovascular protective agents are an integral area of contemporary investigation for RP men who are likely to develop ED. Numerous agents have been investigated, including injectable vasoactive agents and oral phosphodiesterase-5 inhibitors. Recent studies have suggested that thiazolidinediones (TZDs), such as pioglitazone and rosiglitazone, have neurovascular-protective effects. 2 These drugs are used in patients with diabetes mellitus (DM) to decrease insulinresistance. The mechanism of action for treatment of DM involves the upregulation of peroxisome-proliferator-activated-receptor-gamma (PPAR-γ). Other studies have investigated the effects of TZDs in diabetic and aged rats providing intriguing results and demonstrated improved erectile function in alternative pathophysiologic causes of ED. 3,4 New evidence implicates TZDs as having the potential to decrease vascular and smooth muscle damage by up-regulating the expression of Insulinlike Growth-Factor-1 Receptor, and that this effect is accomplished through a PPAR-γ independent mechanism. 5 Since pioglitazone has demonstrated vasculoprotective and anti-fibrotic properties, we hypothesize that pioglitazone is

protective of erectile function in post-prostatectomy ED and may prevent smooth muscle fibrosis. We propose to test our hypothesis by using a validated rat model of post-prostatectomy ED.

Conflicts of Interest None.

Sincerely, Louis A. Aliperti and Wayne J. G. Hellstrom, M.D., F.A.C.S.

References 1. Roupret M, Seisen T, De La Taille A, Desgrandchamps F. Sexual dysfunctions linked with prostatic diseases. Prog Urol 2012;22 Suppl 1:S14-20. 2. Gholamine B, Shafiei M, Motevallian M, Mahmoudian M. Effects of pioglitazone on erectile dysfunction in sildenafil-poor-responders: a randomized, controlled study. J Pharm Pharm Sci 2008;11:22-31. 3. Kovanecz I, Ferrini MG, Vernet D, Nolazco G, Rajfer J, Gonzalez-Cadavid NF. Pioglitazone prevents corporal veno-occlusive dysfunction in a rat model of type 2 diabetes mellitus. BJU Int 2006;98:116-24. 4. Kovanecz I, Ferrini MG, Vernet D, Nolazco G, Rajfer J, Gonzalez-Cadavid NF. Ageing-related corpora venoocclusive-dysfunction in the rat is ameliorated by pioglitazone. BJU Int 2007;100:867-74. 5. Higashi Y, Holder K, Delafontaine P. Thiazolidinediones up-regulate insulin-like growth-factor-1 receptor via a peroxisome-proliferator-activated-receptor-gammaindependent pathway. J Biol Chem 2010;285:36361-8. 6. Usta MF, Bivalacqua TJ, Koksal IT, Toptas B, Surmen S, Hellstrom WJ. The protective effect of aminoguanidine on erectile-function in diabetic rats is not related to the timing of treatment. BJU Int 2004;94:429-32.

Summary Erectile dysfunction (ED) is a common consequence of radical prostatectomy (RP) and can affect a man’s long-term quality of life. Intraoperative manipulation of the neurovascular bundle causes neuropraxia with resultant fibrosis and trabecular smooth-muscle damage. Pioglitazone is an anti-diabetic agent with recognized antifibrotic and vasculoprotective properties, which can protect smooth muscle function. We hypothesize that post-RP pioglitazone therapy can help preserve erectile function.

Pioglitazone prevents cavernosal nerve injury after radical prostatectomy.

Erectile dysfunction (ED) is a common consequence of radical prostatectomy (RP) and can affect a man's long-term quality of life. Intraoperative manip...
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