Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA.
Department of Natural Sciences, Southern University at New Orleans, New Orleans, LA, USA.
J Sex Med. 2019 Mar;16(3):383-393. doi: 10.1016/j.jsxm.2018.12.018.
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.
To eliminate the systemic effects of pioglitazone and evaluate the local delivery of IGF-1 by polymeric microspheres after BCNI in the rat.
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.
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).
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.
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.
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. Haney NM, Talwar S, Akula PK, et al. 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. J Sex Med 2019;16:383-393.
之前的研究表明，在大鼠双侧海绵体神经损伤（BCNI）后使用吡格列酮可以改善勃起功能。我们的研究小组确定这种改善是通过胰岛素样生长因子-1（IGF-1）途径介导的。
消除吡格列酮的全身作用，并在大鼠的 BCNI 后评估 IGF-1 的聚合物微球的局部递送。
10-12 周龄雄性 Sprague-Dawley 大鼠随机分为 3 组：假手术磷酸盐缓冲盐水（PBS）载药微球组（假手术组）、PBS 载药微球挤压伤组（挤压伤组）和 IGF-1 载药微球组（IGF-1 组）。聚（乳酸-共-乙醇酸）微球被注射到主要骨盆神经节（MPG）下。IGF-1 每天约以 30ng/mL/MPG/大鼠的速度释放。
功能结果通过最大海绵体内压（ICP）与平均动脉压（MAP）的比值来证明。使用 Western blot 分析和免疫组织化学法，对海绵体组织和 MPG 和海绵体神经（CN）中的 IGF-1 受体（IGF-1R）、细胞外信号调节激酶（ERK）-1/2 和神经元型一氧化氮合酶（nNOS）的蛋白水平分析数据进行了获取。
在神经损伤后 2 周，与 BCNI 相比，接受 IGF-1 治疗的动物在所有电压下的勃起功能恢复（ICP/MAP）均得到改善（2.5V，P=0.001；5V，P<0.001；7.5V，P<0.001）。Western blot 结果显示，IGF-1R 和 ERK-1/2 在神经和勃起组织中的上调与勃起功能恢复有关。海绵体组织中 nNOS 蛋白水平在各组之间无显著差异，但 MPG 和 CN 中的 nNOS 表达上调。免疫组织化学证实了这些趋势。
在神经损伤时，神经血管床中 IGF-1R 的局部上调可能有助于男性在接受根治性前列腺切除术等骨盆手术后保留勃起功能，从而消除对全身治疗的需求。
本研究表明，MPG 和 CN 的局部药物输送可以影响下游的 CN 组织，但并未研究生长因子受体的上调对前列腺癌组织的潜在影响。
在根治性前列腺切除术后，刺激 CN 中的 IGF-1R 有可能减轻男性的勃起功能障碍，但需要进一步研究以评估这种生长因子在前列腺癌环境下的安全性。
