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Pioglitazone’s beneficial effects on erectile function preservation after cavernosal nerve injury in the rat are negated by inhibition of the insulin-like growth factor-1 receptor: a preclinical study


To determine if the insulin-like growth factor-1 (IGF-1) pathway is involved in the improvement in erectile function recovery in rats after nerve crush injury treated with pioglitazone (Pio). Sprague-Dawley rats were divided into four groups. The first group received sham operation (n = 5). The second group underwent bilateral cavernous nerve injury (BCNI, n  = 7). The third group received BCNI and Pio treatment (BCNI  +  Pio, n = 7), whereas the fourth group underwent BCNI with Pio treatment and IGF-1 inhibition (BCNI  +  Pio  +  JB-1, n = 7). The IGF-1 receptor (IGF-1R) was inhibited by JB-1, a small molecular antagonist of the receptor. After 14 days of treatment, erectile function was measured via intracorporal pressure normalized to mean arterial pressure (ICP/MAP) and the major pelvic ganglion and cavernous nerve harvested for western blot and immunohistochemistry (IHC) of phosphorylated-IGF-1Rβ (p-IGF-1Rβ), phosphorylated-ERK1/2 (p-ERK1/2), and neuronal NOS (nNOS). BCNI  +  Pio animals exhibited improvements in ICP/MAP, similar to Sham animals, and BCNI  +  Pio  +  JB-1 rats demonstrated a reduced ICP/MAP similar to BCNI-only rats at all measured voltages. Western blot results showed upregulation of p-IGF-1Rβ was observed in the BCNI  +  Pio group. Low levels of p-ERK1/2 were seen in the JB-1-treated animals. The immunoblot results were supported by IHC findings. Intense IHC staining of nNOS was detected in the BCNI  +  Pio group. The group treated with JB-1 showed minimal protein expression of p-ERK1/2, nNOS, and p-IGF-1Rβ. Pio improves erectile function in rats undergoing BCNI via an IGF-1-mediated pathway.

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  1. 1.

    Kendirci M, Hellstrom WJ. Current concepts in the management of erectile dysfunction in men with prostate cancer. Clin Prostate Cancer. 2004;3:87–92.

    Article  Google Scholar 

  2. 2.

    Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol. 2016;197:S165–70.

    PubMed  Google Scholar 

  3. 3.

    Schauer I, Keller E, Muller A, Madersbacher S. Have rates of erectile dysfunction improved within the past 17 years after radical prostatectomy? A systematic analysis of the control arms of prospective randomized trials on penile rehabilitation. Andrology. 2015;3:661–5.

    CAS  Article  Google Scholar 

  4. 4.

    Weyne E, Mulhall J, Albersen M. Molecular pathophysiology of cavernous nerve injury and identification of strategies for nerve function recovery after radical prostatectomy. Curr Drug Targets. 2015;16:459–73.

    CAS  Article  Google Scholar 

  5. 5.

    Chung E, De Young L, Brock GB. Investigative models in erectile dysfunction: a state-of-the-art review of current animal models. J Sex Med. 2011;8:3291–305.

    Article  Google Scholar 

  6. 6.

    Quinlan DM, Nelson RJ, Partin AW, Mostwin JL, Walsh PC. The rat as a model for the study of penile erection. J Urol. 1989;141:656–61.

    CAS  Article  Google Scholar 

  7. 7.

    Sundararajan S, Gamboa JL, Victor NA, Wanderi EW, Lust WD, Landreth GE. Peroxisome proliferator-activated receptor gamma ligands reduce inflammation and infarction size in transient focal ischemia. Neuroscience. 2005;130:685–96.

    CAS  Article  Google Scholar 

  8. 8.

    Aliperti LA, Lasker GF, Hagan SS, Hellstrom JA, Gokce A, Trost LW et al. Efficacy of pioglitazone on erectile function recovery in a rat model of cavernous nerve injury. Urology. 2014;84:1122–7.

    Article  Google Scholar 

  9. 9.

    Katz EG, Moustafa AA, Heidenberg D, Haney N, Peak T, Lasker GF, et al. Pioglitazone enhances survival and regeneration of pelvic ganglion neurons after cavernosal nerve injury. Urology. 2016;89:76–82.

    Article  Google Scholar 

  10. 10.

    Smith U. Pioglitazone: mechanism of action. Int J Clin Pract Suppl. 2001;121:13–8.

  11. 11.

    Kintscher U, Law RE. PPARgamma-mediated insulin sensitization: the importance of fat versus muscle. Am J Physiol Endocrinol Metab. 2005;288:E287–91.

    CAS  Article  Google Scholar 

  12. 12.

    Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999;20:649–88.

    CAS  PubMed  Google Scholar 

  13. 13.

    Escher P, Wahli W. Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat Res. 2000;448:121–38.

    CAS  Article  Google Scholar 

  14. 14.

    Higashi Y, Holder K, Delafontaine P. Thiazolidinediones upregulate insulin-like growth factor-1 receptor via a peroxisome proliferator-activated receptor gamma-independent pathway. J Biol Chem. 2010;285:36361–8.

    CAS  Article  Google Scholar 

  15. 15.

    Mughal A, Kumar D, Vikram A. Effects of thiazolidinediones on metabolism and cancer: relative influence of PPARgamma and IGF-1 signaling. Eur J Pharmacol. 2015;768:217–25.

    CAS  Article  Google Scholar 

  16. 16.

    Bochinski D, Hsieh PS, Nunes L, Lin GT, Lin CS, Spencer EM, et al. Effect of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 complex in cavernous nerve cryoablation. Int J Impot Res. 2004;16:418–23.

    CAS  Article  Google Scholar 

  17. 17.

    Sjoberg J, Kanje M. Insulin-like growth factor (IGF-1) as a stimulator of regeneration in the freeze-injured rat sciatic nerve. Brain Res. 1989;485:102–8.

    CAS  Article  Google Scholar 

  18. 18.

    Apel PJ, Ma J, Callahan M, Northam CN, Alton TB, Sonntag WE, et al. Effect of locally delivered IGF-1 on nerve regeneration during aging: an experimental study in rats. Muscle Nerve. 2010;41:335–41.

    CAS  Article  Google Scholar 

  19. 19.

    Sumino Y, Yoshikawa S, Mori K, Mimata H, Yoshimura N. IGF-1 as an important endogenous growth factor for recovery from impaired urethral continence function in rats with simulated childbirth injury. J Urol. 2016;195:1927–35.

    CAS  Article  Google Scholar 

  20. 20.

    Lewis JD, Habel LA, Quesenberry CP, Strom BL, Peng T, Hedderson MM, et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA. 2015;314:265–77.

    CAS  Article  Google Scholar 

  21. 21.

    Govindarajan R, Ratnasinghe L, Simmons DL, Siegel ER, Midathada MV, Kim L, et al. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol. 2007;25:1476–81.

    CAS  Article  Google Scholar 

  22. 22.

    Koro C, Barrett S, Qizilbash N. Cancer risks in thiazolidinedione users compared to other anti-diabetic agents. Pharmacoepidemiol Drug Saf. 2007;16:485–92.

    CAS  Article  Google Scholar 

  23. 23.

    Boxall N, Bennett D, Hunger M, Dolin P, Thompson PL. Evaluation of exposure to pioglitazone and risk of prostate cancer: a nested case-control study. BMJ Open Diabetes Res Care. 2016;4:e000303.

    Article  Google Scholar 

  24. 24.

    Suzuki S, Mori Y, Nagano A, Naiki-Ito A, Kato H, Nagayasu Y, et al. Pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, suppresses rat prostate carcinogenesis. Int J Mol Sci. 2016;17:2027.

  25. 25.

    Erdmann E, Harding S, Lam H, Perez A. Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes Obes Metab. 2016;18:266–73.

    CAS  Article  Google Scholar 

  26. 26.

    Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res. 1998;74:49–139.

    CAS  Article  Google Scholar 

  27. 27.

    Kolch W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J. 2000;351(Pt 2):289–305.

    CAS  Article  Google Scholar 

  28. 28.

    Chattopadhyay S, Shubayev VI. MMP-9 controls Schwann cell proliferation and phenotypic remodeling via IGF-1 and ErbB receptor-mediated activation of MEK/ERK pathway. Glia. 2009;57:1316–25.

    Article  Google Scholar 

  29. 29.

    Rothe F, Langnaese K, Wolf G. New aspects of the location of neuronal nitric oxide synthase in the skeletal muscle: a light and electron microscopic study. Nitric Oxide. 2005;13:21–35.

    CAS  Article  Google Scholar 

  30. 30.

    Carnicer R, Suffredini S, Liu X, Reilly S, Simon JN, Surdo NC, et al. The subcellular localization of neuronal nitric oxide synthase determines the downstream effects of NO on myocardial function. Cardiovasc Res. 2017;113:321–31.

    CAS  Article  Google Scholar 

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Funding for this project was provided by the Sexual Medicine Society of North America.

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Correspondence to Wayne J. G. Hellstrom.

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Heidenberg, D., Haney, N., Rezk, B.M. et al. Pioglitazone’s beneficial effects on erectile function preservation after cavernosal nerve injury in the rat are negated by inhibition of the insulin-like growth factor-1 receptor: a preclinical study. Int J Impot Res 31, 1–8 (2019).

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