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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 5  |  Issue : 3  |  Page : 85-92

The development of rat models induced by cavernous nerve injury


1 Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Andrology, Shanghai, China; Division of Urology, Department of Surgery, University of Texas Medical School at Houston; Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Andrology, Shanghai, China
3 Division of Urology, Department of Surgery, University of Texas Medical School at Houston; Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Date of Web Publication17-Dec-2018

Correspondence Address:
Run Wang
Department of Urology, University of Texas Mcgovern Medical School and MD Anderson Cancer Center, 6431 Fannin Street, MSB 6.018 Houston, Texas 77030
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jina.jina_2_18

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  Abstract 


Background and Objective: Erectile dysfunction (ED) caused by iatrogenic cavernous nerve injury (CNI) is a common complication in males undergoing pelvic surgery. Despite the advances in surgical techniques and the regular administration of phosphodiesterase type 5 inhibitors (PDE5i), recovery from CNI-induced ED remains to be a difficult process. Numerous CNI models have been established to explore the pathogenesis and design effective therapies suitable for human trials. This study aims to examine the studies referring to rat models of CNI induced ED. Methods: A literature review was performed through PubMed using the items “CNI” and “rat model.” We analyzed different types of CNI, the pathophysiology changes after CNI, and current and future strategies of therapy after CNI. Results: A large number of rat models with CNI-induced ED have been established for mimicking ED pathophysiology after radical pelvic surgery. The types of injury include crush, transection, excision, dissection, freezing, electrocautery, and irradiation. The pathophysiological assessments include changes in hemodynamics, nerve structure and morphology, oxidative stress, and inflammation of genes in the corpus cavernosum. The current therapeutic strategies include PDE5i administration, vacuum erection device, and other treatments aiming to decrease known pathologic damages. The future treatment direction may focus on gene transfer, growth factors (nerve and endothelium), cellular scaffolds, and endogenous stem cells to the penis. Conclusions: The CNI rat models are important experimental methods to mimic the nerve damage caused by the treatment of prostate cancer. Many research studies have demonstrated significant pathophysiological changes that occur in rat cavernous bodies after CNI. The ideal model for CNI-induced ED should be explored furthermore to improve the slow recovery of erectile function following CNI.

Keywords: Cavernous nerve injury, erectile dysfunction, rat model


How to cite this article:
Huang YP, Lu MJ, Clavell-Hernandez J, Wang R. The development of rat models induced by cavernous nerve injury. J Integr Nephrol Androl 2018;5:85-92

How to cite this URL:
Huang YP, Lu MJ, Clavell-Hernandez J, Wang R. The development of rat models induced by cavernous nerve injury. J Integr Nephrol Androl [serial online] 2018 [cited 2019 Jun 26];5:85-92. Available from: http://www.journal-ina.com/text.asp?2018/5/3/85/247693




  Introduction Top


Erectile dysfunction (ED) caused by iatrogenic cavernous nerve injury (CNI) is very common in males undergoing pelvic surgeries such as radical prostatectomy (RP), cystoprostatectomy, and colorectal resection. RP is considered to be the standard of care therapy for patients with early-stage prostate cancer, and CNI-induced ED is a serious complication after this procedure. Even with advancements in surgical techniques and equipment, such as nerve-sparing robot-assisted procedures, various degrees of nerve injury still occur. Although phosphodiesterase type 5 inhibitors and vacuum erection device (VED) are commonly used to treat CNI-induced ED, the efficacy of these therapies in these patients are not expected to be as high as in the general ED population.[1] Thus, neurogenic ED associated with pelvic surgery is still particularly difficult to treat, and therapeutic strategies should be further developed to restore CN integrity and rehabilitate erectile function.

The theory of penile erection physiology originated from in vivo and in vitro experiments on animals. Since the first erectile stimulation experiment conducted in an anesthetized dog by Eckhard in 1863,[2] many models of different animals such as cats, monkeys, dogs, and rabbits were used to mimic human erectile response. As the intracavernosal pressure (ICP) measurements in smaller animals such as mice and rats became commercially available, in vivo models rapidly developed in the research for various diseases and injuries. The practicability and economic advantages enabled rat models to be the most popular model for mimicking ED pathophysiology after radical pelvic surgeries. So far, researchers have been able to establish a number of CNI models used to explore the pathogenesis of ED and design effective therapies suitable for human trials. This article aims to review the literature of experimental rat models of CNI and analyze its current development.


  Methods Top


We searched the literature, including original research work and certain review articles, on the National Library of Medicine PubMed services. The search terms used were “CNI” and “ndu model.” The available literature consisted of peer-reviewed articles in the English language. All cited articles were identified by the careful review.

Cavernous nerve injury model establishment

Quinlan et al.[3] were the first to develop a penile erection test in a rat model. The establishment of the CNI model usually requires setting control groups, such as sham and vehicles. In the sham group, pelvic surgery was done only to expose the major pelvic ganglia (MPG) and CNs; whereas in the CNI group, the exposed CN is impaired. A vehicle group is usually designed for treatment, such as CNI + vehicle versus CNI + therapy. The selection of injury types and unilateral versus bilateral injury depend on the research purpose.

Cavernous nerve injury types

The CNI types are mainly classified as crush, transection, and excision in traditional rat models.[4] In recent years, dissection, freezing, electrocautery, and irradiation were also introduced by some researchers [Table 1]. The two severe types of injury, transection, and excision, aim to destruct the continuity of CN. In the transection injury, CNs were sheared, and both sides of the broken ends were in a free state.[5],[6],[7] In the excision injury, the CN was cut into two sections, and the middle segment of the nerve was removed.[10],[11],[12] Transection and excision models are designed to mimic the loss of erectile function following non-nerve-sparing RP in humans. Currently, most researchers prefer CN crush injury which is believed to produce the least amount of damage. A crush injury, which involves compression of the nerve, is considered to be the closest representation to the partial nerve damage caused by nerve-sparing RP. The severity of the damage in the model depends on the type of instrument (e.g., forceps or hemostatic clamp) used and the compression time (e.g., from 15 s to 2 min).[14],[15],[23],[24] In the dissection model described by Yamashita et al., the CNs were dissected bilaterally from the MPG to the apex of the prostate without crushing or cutting.[25] Compared to the CN excision model, they believe that CN dissection model might be more conducive to clarify the mechanism of nerve injury-related ED and the recovery from ED after nerve-sparing RP.[25],[26],[27]
Table 1: Characteristics in different types of cavernous nerve injury rat models

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Freezing is conducted by using a disposable centrifuge tube containing dry ice or liquid nitrogen.[28],[29] Freezing injury does not disrupt the nerve sheath, which benefits the regeneration of nerve axons.[29],[30] On the other hand, electrocautery injury is used to mimic the damage induced by monopolar electrocautery during the operation.[30],[31] CN electrocautery injury was induced by consistently applying a monopolar electrocautery tip connected to an electrocautery generator on the main branch of the CNs, 5 mm distal to the MPG, on both sides of the prostate. The monopolar electrocautery was performed for 1 s at 350 kHz and 15W.[30]

Radiation therapy (RT) has been applied in clinical treatment programs for prostate cancer. Acceptable and validated animal models mimicking current clinical RT settings are crucial to advance translational research in radiation biology. Kimura et al.[32] introduced a new technology for small-animal research in radiation biology using a cone-beam computed tomography-based small-animal image-guided irradiation unit. In the process of establishing a rat model, Sprague-Dawley rats were randomly divided into three groups for prostate irradiation with doses of 15, 20, and 25 Gy, respectively.[32],[33],[34]

Unilateral versus bilateral cavernous nerve injury

The selection of unilateral versus bilateral injury depends on the purpose of the experimenter. Canguven and Burnett[4] had reviewed the literature and compared this two types of CNI. The unilateral CNI model can serve as its own control, in other words, the injured and sham groups are in the same animal at the same time.[8] Therefore, the advantage for unilateral CNI model is that it allows investigators to compare injured and sham ICP results in the same animal independent of mean arterial pressure (MAP).[6] However, this type of model is likely to contain remnants of erectile function, compensatory nerve sprouting, and effects of neurotrophic factors transferred from the contralateral uninjured side, which may confound experimental interpretations.[35] Bilateral CNI abrogates nerve innervation and removes compensatory sprouting from the contralateral CN. It also excludes the possibility of erection responsiveness supported by the intact contralateral CN in unilateral nerve injury. As bilateral CNI completely interrupts transmission of neurotrophic factors and maintenance of homeostasis within the tissue, it eliminates the confounding effects of unilateral CNI.[4]

Unilateral CNI can be utilized as an animal model for unilateral nerve sparing pelvic surgeries, but this is not exactly in line with clinical practice. Many researchers believe that bilateral CN crush injury best represents nerve-sparing RP, and bilateral CNI has the advantage for long-term morphologic studies of the penis.[24],[36]

Cavernous nerve injury model evaluation

A successful animal model needs to be confirmed by some special indicators. In the CNI model, decreased erectile response and nerve damage are the two vital markers. Furthermore, corpora cavernosum pathophysiological parameters, oxidative stress, inflammation markers, and genome were also evaluated for the study of pathological mechanisms and treatments. The main evaluation items in recent studies of CNI rat models were listed in [Table 1].

Intracavernosal pressure test

Monitoring ICP is the primary test item that examines the erectile function of the penis in the rat model studies.[3],[37] The erection for ICP monitoring can be induced by electrical stimulation of CN or vasoactive drug injections.[38],[39] Intracavernosal administration of papaverine is a common method to elicit an erection.[37],[39] Kaufmann et al.[9] introduced a method using apomorphine injections in the loose skin of the back of the neck to elicit penile erections. This method was based on the fact that microinjection of apomorphine (a dopamine agonist) causes the dopamine receptor in the paraventricular nucleus of the hypothalamus to be stimulated and therefore induces a penile erection. However, given that the electrical stimulation method using a bipolar electrode hooked onto the CN is easily accomplished and reproducible, this has become the universal technique. In their rat model experiment, Martínez-Piñeiro et al. found that an electrical stimulation with 20 pulses per se cond (PPS) and 1.5 mA in CN may elicit maximal erectile responses, and stimulation frequencies below 20 PPS (10 and 5 PPS) may induce a longer erection response.[38] The ICP tests need to record parameters that include number of erections, tumescence time, detumescence time, duration of response, basal ICP, peak ICP, and plateau ICP. The area under the ICP curve needs to be recorded in the period of monitoring time. In fact, the application of a single parameter ICP to evaluate erectile function is not accurate. Mills et al.[40] found that ICP can be affected by systemic hemodynamics, thus the measured ICP should be adjusted by the MAP and transferred as ICP/MAP. All aspects of the ICP response should be normalized to MAP as “normalized ICP or normalized ICP area under the curve.” MAP can be measured by aorta cannulation (e.g., carotid artery).

Nerve damage and regeneration assessment

Nerve damage is the vital pathological abnormality in a successful CNI model, which is reflected by the structure and morphology changes of MPG and its branching CNs. Palma and Keast[6] found that sprouting of injured postganglionic axons in the pelvic ganglia of adult male rats occurs concurrently with structural or chemical changes in preganglionic terminals. Many sprouting fibers formed close associations with sympathetic and parasympathetic pelvic neurons. Preganglionic terminals showed a marked loss of synaptic proteins, suggesting a retrograde effect of the injury beyond the injured neurons.

Fluorogold (FG) is a fluorescent tracer which can be used to assess the degree of nerve damage and nerve regeneration effectively.[41],[42] If the nerve remains intact in a target organ, the injected FG can be transported in retrograde fashion from the nerve terminals to the nerve cell bodies. FG-positive neurons in the dissection group were significantly decreased at 4 weeks after surgery compared with the sham group.[25]

Moreover, as CNI interrupts the transmission of neurotrophic factors and maintenance of homeostasis within the tissue, the change in neuronal transmitters can be used to identify the CNI. Nitric oxide (NO) is a neuronal transmitter-like messenger and physiologic mediator of erections, thus there is a large amount of NO synthase (NOS) expression in the corpus cavernosum. In a successful CNI rat model, the expression and immunoreactivity of nNOS commonly present a significant decrease. El-Sakka et al.[28] also found that after unilateral CNI, there was a significant decrease of eNOS and iNOS expression in the dorsal and intracavernosal nerves and ipsilateral pelvic ganglia as compared with the intact side.

Neurturin (NTN) and glial cell line-derived neurotrophic factor (GDNF) are neurotrophic factors for penile parasympathetic neurons. The altered expression of receptors for members of the GDNF family (e.g., GFRα1 and GFRα2) can be used to verify CN and MPG injuries. NTN has been shown to have multiple neurotrophic actions on adult rat pelvic parasympathetic ganglion neurons in vitro.[43] GDNF is also relevant for maintenance of penile innervation; many penile neurons express GFRα1 and transport GDNF in retrograde fashion within the penis.[44] Palma and Keast's study also demonstrated that GFRα2 immunofluorescence intensity was decreased in the cytoplasm of parasympathetic neurons in CNI rat models.[6]

Tyrosine hydroxylase (TH) is an indicator of sympathetic activity, and over-expressed TH may cause nerve fiber hyper-regeneration in the corpus cavernosum and induce a decrease in nNOS-positive fibers in the dorsal nerve. Some studies have demonstrated that CNI rat models presented a significant increase in TH-positive nerve endings.[14],[24] Furthermore, the expression of markers for parasympathetic (Choline Acetyltransferase) and the neuronal marker (β IIITub) can be also used to determine the degree of nerve damage. Hannan et al. found that these markers decreased by 50% within 48 h of CNI.[16]

The immunosuppressant FK506 has also been used to evaluate nerve damage as it has a role in promoting nerve regeneration and function.[45] Many studies demonstrated that administration of FK506 benefits neuroprotection and erectile function preservation in CNI rats.[46],[47],[48],[49] In addition, neural growth factor (NGF), a multifunctional secreted polypeptide in the neurotrophin family, plays an important role in the growth, maintenance, and survival of certain target neurons. Thus, both NGF and its receptors neurotrophic tyrosine kinase receptor type 1 (TrkA) can be used to assess acute and chronic nerve injury states.[50],[51]

Corpora cavernosum pathophysiology

Cell apoptosis is a common pathological phenomenon in CNI models. Lysiak et al. found that penile smooth muscle cells (SMCs) and endothelial cells (ECs) presented with significant levels of apoptosis at 2 weeks after bilateral CN transection and the degree of apoptosis increased even more after 4 and 6 weeks.[52] Cavernous SMCs (CSMCs) in CNI rats may suffer hypertrophy and present rough endoplasmic reticulum formation. Yang et al.[26] demonstrated that the expression of CSMCs phenotypic markers, such as smooth muscle a-actin, smooth muscle myosin heavy chain, and desmin were markedly lower, whereas vimentin protein expression was significantly higher after bilateral CNI. In radiation-induced injury rat models, the expression levels of anti-alpha smooth muscle actin and endothelial NOS in CC were significantly decreased at 9 weeks, and smooth muscle/collagen ratio in penile dorsal vessels were also significantly decreased at 4 and 9 weeks,[34] which was also supported by the CN electrocautery injury rat model conducted by Song et al.[30] As the CSMCs and cavernous ECs apoptosis and fibrosis increase, corporal veno-occlusive dysfunction increases in the CNI rats. Compared with a sham group, rats with bilateral CN excision demonstrated corporal veno-occlusive dysfunction. This was measured with dynamic infusion cavernosometry which revealed a drop rate of almost two-fold.[53] In a study by Kimura et al., Hoechst perfusion analysis showed a time-dependent decrease in corpora cavernosa of radiation-treated animals, whereas CD31 expression was not affected.[34] Cho et al.[15] systemically studied the process of corporal veno-occlusive dysfunction. They observed increased apoptosis, decreased immunohistochemical staining of alpha-smooth muscle actin and increased caspase-3 activity in the group undergoing CNI. Simultaneously, a significantly decreased smooth muscle-to-collagen ratio and increased fibroblast pCofilin were also noted in the injury group. Eventually, they demonstrated that early inhibition of Rho-kinase after CNI may prevent corporal apoptosis and fibrosis by suppressing the Akt/Bad/Bax/caspase-3 and LIMK2/cofilin pathways, which would prevent corporal veno-occlusive dysfunction and ED.

Oxidative stress and inflammation

Oxidative stress and inflammation play an important role in the pathophysiological development of CNI. Wang et al. found that two main oxidative stress markers, superoxide dismutase (SOD), and glutathione peroxidase (GPX), increased in CNI rats at early time points. NADPH-diaphorase staining was used to identify NOS in the penile dorsal nerve fibers. The study showed that NADPH-diaphorase-positive nerve fibers were statistically decreased among groups. Furthermore, the transection group showed greater oxidative stress than the crushed group, and GPX expression and nitrotyrosine-3 (NT-3) levels in penile tissue were in concordance with the results of SOD and GPX.[7] The study of Kim et al.[22] showed there was increased expression of hypoxia-inducible factor-1a and decreased expression of eNOS and nNOS in bilateral CNI models.

In the radiation injury rat model, Kimura et al. found oxidative stress was accompanied by inflammation. In their study, the markers of oxidative DNA damage (8-hydroxy-2′-deoxyguanosine) and lipid peroxidation (4-hydroxynonenal) increased with the increased expression of NADPH oxidase subunits (Nox4 and gp91phox). They also noted that inflammatory responses including iNOS, macrophage activation (ED-1), and nitrotyrosine were also found in tissues after RT.[33] Moreover, Matsui et al.[20] found that gene expression of proinflammatory (Il1b, Il16, Tnfa, Tgfb, Ccl2, and Ccr2) and anti-inflammatory (Il10) cytokines were up-regulated in the MPG 48 h after injury.

Genetic changes

Calenda et al.[21] make a whole genome microarray analysis for the CNI rat model. They found that 325 genes and 114 genes were differentially expressed in MPG at 48 h and 14 days after CNI, respectively. A comparative analysis of the changes on gene expression occurring 48 h and 14 days after CNI shows that 60 genes are commonly changed, 265 genes are unique to 48 h and 54 genes are unique to 14 days. The specific function of changed genes mainly correlated to repair and neuroprotection mechanisms (SERPINF1, IGF1, PLAU/PLAUR, ARG), nervous system development (ATF3, GJA1, PLAU, SERPINE1), nerve regeneration (SERPINE2, IGF1, ATF3, ARG1), and synaptic transmission (GJC1, GAL). Several genes related to proliferation and apoptosis (A2M, ATF3, C3, EGR4, FN1, GJA1, GAL) were also changed, possibly as part of a protective mechanism or the initiation of remodeling. Kam et al.[13] identified 46 genes that were up-regulated and 77 genes that were down-regulated in both the CNI- and diabetes-induced ED models. In the CNI-induced ED model, gene signatures related with reproductive process, anatomical structure development, system development, and negative regulation of the developmental process were downregulated.

Current status and future directions of therapy in cavernous nerve injury

The damaged peripheral nervous system is hard to regenerate; thus, the detrimental changes and functional failure of the end organ are usually inevitable. Currently, the therapeutic strategies mainly focus on the pathophysiologic changes after CNI, which include nerve repair and regeneration, corpus cavernosum structure and morphology recovery, anti-oxidation treatment, anti-inflammatory treatment, and gene modification. PDE5 inhibitors[54] and VED[55] are the most common therapy strategies for CNI-induced ED. These treatment modalities are considered to have beneficial effects in penile rehabilitation by reducing penile hypoxia,[56] apoptotic index and fibrosis,[57] decreasing oxidative stress and inflammation,[58] increasing penile smooth muscle replication and smooth muscle: collagen ratio,[53] preserving penile endothelial function, and preventing veno-occlusive dysfunction.[59] A novel technique low-energy shock wave has also been shown to treat ED in clinical practice and is currently considered to be effective in the recovery of ED after CNI.[60],[18] Furthermore, annexin1,[17] COX2-10aa-PGIS gene,[61] icariin,[62] pioglitazone,[63] tissue sealing sheet,[27] Rho-Kinase inhibitors,[15] and PnTx2-6[64] have also been found to be beneficial in improving penile structure and function after CNI. Researches have also investigated strategies to enhance neuroregeneration or increase neuroprotection of the CNs to minimize the damage of CN denervation, such as immunomodulatory therapy (e.g., FK506, rapamycin, and cyclosporin) and neurotrophic factor therapy (e.g., BDNF, NGF, NT3, and NT4).[65] Bella et al. reviewed the literature and found that many of these strategies have shown beneficial effects in CNI animal models.[66] Recently, docosahexaenoic acid,[67] glial growth factor-2 (GGF2),[68] and neurotrophic TrkA monoclonal antibody[14] were demonstrated to have a neuroprotective role in the CNI rat models. Stem-cell therapy has become a popular treatment direction, and it can provide a realistic therapeutic strategy for the treatment of ED although there are still some limitations applying to clinical practice. Currently, the mechanisms of stem cells treatment include differentiation and cavernosal tissue incorporation, paracrine role on surrounding smooth muscle, neurons, and endothelium; and regeneration of penile tissue.[19],[69],[70] In view of the current bottleneck of stem cell research, the future therapy may focus on the most efficient strategies using gene transfer, growth factors (nerve and endothelium), cellular scaffolds, and endogenous stem cells of the penis to acquire the best therapeutic effect. Although many preclinical strategies that promote erectile function recovery have been investigated in the rat model and have acquired gratifying results in basic research, continuous efforts are still warranted to explore the optimal type of rat model mimicking the disorders of sexual function in humans. We believe rat models will continue to be an essential research tool to discover and test novel therapeutic agents and surgical procedures in the field.


  Conclusions Top


CNI rat model is designed to mimic the injury after pelvic surgery or radiation treatment, especially for the treatment of prostate tumors. There are many types of CNI methods, such as crush, transection, and excision in traditional methods, and dissection, freezing, electrocautery, and irradiation in recently developed methods. The crush injury is the most popular model and is believed to be the best to represent nerve-sparing RP in humans. Bilateral CNI has the advantage over unilateral CNI to assess erectile function in long-term studies of the penis. The radiation-induced injury model has gradually attracted attention due to the development of prostate RT. CNI can cause direct pathophysiological changes including ICP decreasing and CN damage, and indirect pathophysiological changes including cell apoptosis, tissue fibrosis, oxidative stress, inflammation, and veno-occlusive dysfunction. The current therapeutic strategies mainly focus on the direct and indirect pathophysiological mechanisms. As the pathophysiological mechanism after CNI and erectile function recovery remain to be unclear, an ideal model for CNI-ED will continue to be an essential tool for researchers.

Financial support and sponsorship

This work was funded by the grant from the National Natural Science Foundation of China (No. 81401196).

Conflicts of interest

There are no conflicts of interest.



 
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