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Have you read? Best of the best: basic research

Nuno Louro
University of Porto (ICBAS-UP)
Porto, Portugal
Urology Department of Centro Hospitalar e Universitário do Porto (CHUP) Porto, Portugal

Female Sexual Dysfunction

Hernández-Munive AK, Rebolledo-Solleiro D, Fernández-Guasti A. Does chronic hyperglycemia affect female rat sexual behaviour? Differences in paced and non-paced mating.
J Sex Med. 2019; 16: 1130-42.

Type 2 diabetes mellitus (DM) has been clearly associated with male sexual dysfunction, but its role in female sexuality has been more controversial and few studies have evaluated the impact of DM on desire and excitement. The authors designed this study to determine, in a model that simulates DM type 2, the impact of chronic hyperglicemia on female rats receptivity, proceptivity, and aggressiveness. They used 37 hyperglicemic female rats (treated with streptozocin in the neonatal period) and 37 female rats as control. Their sexual behaviour (in paced mounting and non-paced mounting) was evaluated at week 12 of life. The authors found a reduced proceptivity in the DM model female rat, depending on their hormonal condition, suggesting that chronic hyperglicemia produces decreases in sexual behaviour.

Erectile Dysfunction

Kim SW, Lee J, Park J, et al. Combination of LIM-kinase 2 and Jun amino-terminal kinase inhibitors improves erectile function in a rat model of cavernous nerve injury.
Urology. 2019; 131:136-43.

Despite the advances in surgical techniques, the rates of erectile dysfunction (ED) after radical prostatectomy (RP) remain very high, with significant adverse impact on quality of life of patients with prostate cancer. The exact pathophysiology remains to be elucidated but cavernosal apoptosis and fibrosis, resulting from lack of erections in postoperative period, seem to play a role. The clinical role of penile rehabilitation with standard ED therapies is far from convincing so mechanism-specific therapies may be necessary to improve erectile function recuperation after RP. The authors had previously suggested that the target molecular pathway for cavernosal apoptosis and fibrosis could be Jun-amino terminal kinase (JNK) signalling and LIM-kinase 2 (LIMK2) inhibition, respectively. Targeting these pathways separately improved ED but failed to normalize erectile function and this led the authors to hypothesize that a combination therapy could be a useful strategy for this condition. To test this hypothesis they used sixty male Sprague-Dawlwy rats categorized in 4 groups: sham-surgery, cavernosal nerves crush injury, cavernosal nerves crush injury treated with a combination of LIMK2-inhibitors and low-dose JNK-inhibitors and cavernosal nerves crush injury treated with a combination of LIMK2-inhibitores and a high dose of JNK-inhibitors. The erectile response was investigated 10 days after surgery, and they also performed histological and Western-blot studies. They found that dual inhibition of JNK and LIMK2 significantly improved erectile function by suppression of cavernosal apoptosis and fibrosis via restoration of JNK and LIMK2/Cofilin pathways.

Gu X, Shi H, Matz E, et al. Long-term therapeutic effect of cell therapy on improvement of erectile function in a rat model with pelvic neurovascular injury.
BJU Int. 2019; 124: 145-54

Cell therapy has provided a promising outcome for improvements of erectile function in pre-clinical studies and human clinical trials. Several types of stem cell populations have been studied in short and middle-term experiments but not in long-term follow-up. The objective of the present study was to determine the long-term therapeutic effect among three types of human cell types on erectile function recovery in a rodent model of dual neurovascular injured erectile dysfunction (NVED). This model was established in athymic rats by crushing the bilateral cavernous nerves and ligating the internal pudendal nerve-vessel bundles. At the time of the defect creation, they injected intracavernously three different types of human cell populations (umbilical vein endothelial cells, adipose derived stem cells and amniotic fluid derived stem cells. The control group was injected with saline. They assessed erectile function and performed histomorphological analyses 12 weeks after. They found that the ratio of intracavernous pressure to mean artery pressure significantly increased in the cell therapy groups, compared to the saline injection group. Immunofluorescence staining showed increased numbers of cells expressing biomarkers of endothelial, smooth muscle, and nerve cells within the penile tissue in the cell therapy group when compared to the saline injection group.

Tang Z, Song J, Yu Z, et al. Melatonin treatment ameliorates hyperhomocysteinemia-induced impairment of erectile function in a rat model.
J Sex Med. 2019; 16: 1506-17

Hyperhomocysteinemia (HHcy) has been reported to be strongly correlated with the occurrence of erectile dysfunction (ED), although the mechanisms are not fully understood. One of the possible mechanisms could be through enhancing oxidative stress. In past decades a close relationship between melatonin and HHcy has been discovered, and several reports have provided evidence that melatonin could regulate the total Hcy level and protect the cells against HHcy induced toxicities. Based on this, and the antioxidant, antiapoptosis and vascular protective functions of melatonin, the authors hypothesized that melatonin could be applied as a potential treatment method for ED. They used a Sprague-Dawley rat model of HHcy, induced by a 7% methionine-rich diet. Thirty-six male rats were randomised in 3 groups: control group, 7% methionine group and 7% methionine and melatonin group. After 4 weeks they evaluated the rats erectile function (by electric stimulation of the cavernous nerve) and analysed histologic and molecular alterations of the corpus cavernosum. They found that melatonin could preserve erectile function mainly through inhibition of oxidative stress via the Erk1/2/Nrf2/HO-1 signaling pathway and suppression of apoptosis. The authors concluded that melatonin could be a potential therapeutic method for HHcy-related ED.

Wortel RC, Mizrachi A, Li H, et al. Sildenafil protects endothelial cells from radiation-induced oxidative stress.
J Sex Med. 2019; 16: 1721-33

The etiology of radiation-induced erectile dysfunction (ED) is complex and multifactorial, and it appears to be mainly atherogenic. The aim of this study was to focus on vascular aspects of radiation-induced ED and to elucidate whether the protective effects of sildenafil that have been suggested by some authors are mediated by attenuation of oxidative stress and apoptosis in the endothelial cells. They used bovine aortic endothelial cells (BAECs), with or without pretreatment of sildenafil to test endothelial dysfunction in response to external beam radiation and studied the generation of reactive oxygen species (ROS). The authors measured extracellular and intracellular hydrogen peroxide (H2O2). ROS superoxide was also measured. Both H2O2 and superoxide are known to reduce the bioavailability of nitric oxide, which is the most significant chemical mediator of penile erection. Generation of cellular peroxynitrite was measured using a chemiluminescence assay with the PNCL probe. Subsequently, they measured the activation of acid sphingomyelinase (ASMase) enzyme and the generation of the proapoptotic C16-ceramide was assessed. Endothelial cells apoptosis was measured as a readout of these cells’ dysfunction. The authors demonstrated that single high-dose radiation therapy induced NADPH oxidases (NOXs) activation and ROS generation via the proapoptotic ASMase/ceramide pathway. In addition, they showed that sildenafil significantly reduced radiation-induced superoxide and as a result there was reduction in the generation of peroxynitrite in these cells. The authors concluded that sildenafil protected the endothelial cells from radiation therapy-induced apoptosis and propose that these studies should be followed in an animal model of ED.

Premature Ejaculation

Ongün S, Acar S, Koca P, et al. Can botulinum-A toxin be used to delay ejaculation: results of an ejaculation model in male rats.
J Sex Med. 2019; 16: 1338-43.

The bulbospongiosus (BS) muscle seems to be closely associated with ejaculation latency. Botulinum toxin leads do flaccid paralysis in muscle by preventing the release of acetylcholine on the presynaptic nerve end at the neuromuscular junction. The authors hypothesized that the inhibition of contractions of the BS muscle by botulin toxin might have a beneficial effect in the treatment of premature ejaculation (PE). They randomly divided 21 Wistar male rats in 3 groups of 7: control, 1 unit of botulin-A toxin injected, and 5 units of botulin-A injected. Five days after the botulin-A toxin injection, the rats underwent surgery to evaluate ejaculation parameters induced by para-chloroamphetamine (PCA) injection. They found that the ejaculation latency time of the group receiving 5 units of botulinum-A toxin was statistically significantly longer compared to the control group and the group receiving 1 unit of botulinum-A toxin. Furthermore, the BS EMG area under the curve values for the group receiving 5 units of botulinum-A toxin were significantly lower than those of the control group and the group receiving 1 unit of botulinum-A toxin. Although the present study didn´t use a PE model, the authors conclude that botulinum-A toxin could be a potential treatment for PE and encourage further investigation in clinical studies.

Peyronie’s Disease

Castiglione F, Hedlund P, Weyne E, et al. Intratunical injection of stromal vascular fraction prevents fibrosis in a rat model of Peyronie´s disease.
BJU Int. 2019; 124: 342-48

Since there are no evidence-based treatment options for the acute phase of Peyronie´s disease (PD), we always welcome the research in this field. Several studies have recently suggested a possible role of mesenchymal stem cells (MSCs) in the treatment of corpus cavernosum fibrosis and PD. Although the exact mechanisms behind the anti-fibrotic properties of MSC therapy remain to be elucidated, the leading theory is that MSCs influence various pro-fibrotic parameters simultaneously, working through immunomodulation, thereby limiting the host response to injury and preventing the onset of fibrosis. This group has previously showed the efficacy of human adipose tissue derived MSC (ADSC) in preventing fibrosis in a rat model of acute phase PD. ADSCs are isolated as part of the aqueous fraction derived from enzymatic digestion of lipoaspirate (the product of liposuction). This aqueous fraction, a combination of ADSCs, endothelial precursor cells, endothelial cells, macrophages, smooth muscle cells, lymphocytes, pericytes, and pre-adipocytes among others, is what is known as the stromal vascular fraction (SVF). In the current study, they investigated the effects of an early local injection of SVF on plaque formation and erectile function in a rat model for the acute phase of PD. A total of 24 male Sprague-Dawley rats were divided in three equal groups: sham, PD without treatment (TGFB) and PD treated with SVF (SVF) 1 day after disease induction. Sham rats underwent 2 injections of vehicle into the tunica albuginea one day apart. TGFB rats underwent TGF- β1 injection and injection of vehicle one day later. SVF rats underwent TGF-β1 injection followed by SVF one day later. One month after treatment all rats underwent measurement of intracorporal pressure (ICP) and mean arterial (MAP) pressure during electrostimulation of the cavernous nerve. Following euthanasia, penises were again harvested for histology and Western blot. They showed that erectile function was moderately reduced in the TGFB group and was significantly improved after SVF treatment (p < 0.05). PD animals developed areas of fibrosis with a significant upregulation of collagen III, Collagen I and elastin protein expression. These fibrotic changes were prevented when treated with SVF. These results encouraged the authors to conclude that local injection of SVF may represent a treatment for the acute phase of PD.