Insulin-Like Growth Factor-1–Loaded Polymeric Poly(Lactic-Co-Glycolic) Acid Microspheres Improved Erectile Function in a Rat Model of Bilateral Cavernous Nerve Injury

Abstract

Background Previous studies have documented improvement in erectile function after bilateral cavernous nerve injury (BCNI) in rats with the use of pioglitazone. Our group determined this improvement to be mediated by the insulin-like growth factor-1 (IGF-1) pathway. Aim To eliminate the systemic effects of pioglitazone and evaluate the local delivery of IGF-1 by polymeric microspheres after BCNI in the rat. Methods Male Sprague–Dawley rats aged 10–12 weeks were assigned at random to 3 groups: sham operation with phosphate buffered saline (PBS)-loaded microspheres (sham group), crush injury with PBS-loaded microspheres (crush group), and crush injury with IGF-1–loaded microspheres (IGF-1 group). Poly(lactic-co-glycolic) acid microspheres were injected underneath the major pelvic ganglion (MPG). IGF-1 was released at approximately 30 ng/mL/day per MPG per rat. Outcomes Functional results were demonstrated by maximal intracavernosal pressure (ICP) normalized to mean arterial pressure (MAP). Protein-level analysis data of IGF-1 receptor (IGF-1R), extracellular signal–regulated kinase (ERK)-1/2, and neuronal nitric oxide synthase (nNOS) were obtained using Western blot analysis and immunohistochemistry for both the cavernosal tissue and the MPG and cavernous nerve (CN). Results At 2 weeks after nerve injury, animals treated with IGF-1 demonstrated improved erectile functional recovery (ICP/MAP) at all voltages compared with BCNI (2.5V, P = .001; 5V, P < .001; 7.5V, P < .001). Western blot results revealed that up-regulation of the IGF-1R and ERK-1/2 in both the nervous and erectile tissue was associated with improved erectile function recovery. There were no significant between-group differences in nNOS protein levels in cavernosal tissue, but there was an up-regulation of nNOS in the MPG and CN. Immunohistochemistry confirmed these trends. Clinical Translation Local up-regulation of the IGF-1R in the neurovascular bed at the time of nerve injury may help men preserve erectile function after pelvic surgery, such as radical prostatectomy, eliminating the need for systemic therapy. Strengths & Limitations This study demonstrates that local drug delivery to the MPG and CN can affect the CN tissue downstream, but did not investigate the potential effects of up-regulation of the growth factor receptors on prostate cancer tissue. Conclusion Stimulating the IGF-1R at the level of the CN has the potential to mitigate erectile dysfunction in men after radical prostatectomy, but further research is needed to evaluate the safety of this growth factor in the setting of prostate cancer.

Intracavernous Injection of Autologous Platelet-Rich Plasma Ameliorates Hyperlipidemia-Associated Erectile Dysfunction in a Rat Model

“…8 These cytokines have been shown to ameliorate impaired penile hemodynamics in animal models of ED. 25,26 We selectively measured the concentrations of IGF-1, BDNF, bFGF, and VEGF in our PRP product and found that it was rich in these trophic factors. Additional studies to verify the molecular mechanisms underlying the relationship among PRP, cytokines, and ED are warranted.…”

Insulin-Like Growth Factor-1: A Promising Therapeutic Target for Peripheral Nerve Injury

“…In addition to the pre-soaked IGF-1 eluting hydrogels detailed in Table 6 , several bioengineering approaches to local IGF-1 delivery have recently been reported in animal models. Notable amongst these studies are a delivery system which makes use of biodegradable poly(lactic-co-glycolic acid) (PLGA)/graphene oxide (GO) nanofibers embedded with immobilized IGF-1 for spinal cord repair, as well as a system of IGF-1 loaded polymeric PLGA microspheres for use in bilateral cavernous nerve injury ( Santos et al, 2016 ; Haney et al, 2019 ; Pan et al, 2019 ).…”

Comparison of critical biomarkers in 2 erectile dysfunction models based on GEO and NOS-cGMP-PDE5 pathway

“…[ 4 ] Both DMED and CNIED rat models are commonly used. [ 5 , 6 , 29 , 30 ] Using CNIED rat model, a study showed that sildenafil, as a PDE5 inhibitor (PDE5i), can attenuate gene expression on inflammatory and oxidative stress related-pathways. [ 29 ] Some genome-wide and computational studies provided the groundwork for understanding complex mechanisms and molecular signature changes in different ED, [ 11 ] but little is known from the point of NOS-cGMP-PDE5 pathway, especially the subtypes of NOS.…”

“…[ 5 ] The commonly used method to create CNIED model is to squeeze, freeze, or cut off unilateral or bilateral cavernous nerves. [ 6 ] Vascular and psychological ED animal models were also established according to different etiology. [ 7 , 8 ] Many bioinformatics technologies have been used to compare the above ED models from the point of genetics, [ 9 – 11 ] such as differentially expressed genes (DEGs) analysis between CNIED and DMED rat models.…”