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

• Published in: International journal of impotence research Vol. 31; no. 1; pp. 1 - 8
• Main Authors: Heidenberg, Daniel J., Haney, Nora M., Rezk, Bashir M., Talwar, Sudha, Okpechi, Samuel C., Srivastav, Sudesh K., Honda, Matthew, Song, Bryant, Swan, Kevin, Awadallah, Salah, Anaissie, James, Peak, Taylor, DeLay, Kenneth J., Kadowitz, Phillip J., Sikka, Suresh C., Abdel Mageed, Asim B., Hellstrom, Wayne J. G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2019; Nature Publishing Group
• Subjects: 101/1; 13/51; 692/699/2768/1575; 692/699/2768/1753; 82/1; 82/51; 82/80; Animals; Dosage and administration; Drug therapy; Erectile dysfunction; Erectile Dysfunction - drug therapy; Erectile Dysfunction - etiology; Ganglion cysts; Gene expression; Hypoglycemic agents; Immunohistochemistry; Impotence; Injuries; Insulin; Insulin-like growth factor I; Insulin-like growth factors; Male; Males; Medicine; Medicine & Public Health; Nerve Crush; Nervous system; Nervous system diseases; Neurons; Nitric Oxide Synthase Type I - metabolism; Penile Erection - drug effects; Peripheral Nerve Injuries - complications; Phosphorylation - drug effects; Pioglitazone; Pioglitazone - pharmacology; Pioglitazone - therapeutic use; Rats; Rats, Sprague-Dawley; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - metabolism; Reproductive Medicine; Rodents; rology; Sexual disorders; Signal Transduction - drug effects; Thiazolidinediones; Up-Regulation - drug effects; Urology
• ISSN: 0955-9930; 1476-5489
• DOI: 10.1038/s41443-018-0054-2

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.