Engin Seçkin, Barut Elif Nur, Kaya Yaşar Yeşim, Işık Semanur, Kerimoğlu Gökçen, Burnett Arthur L, Sezen Sena F
Department of Pharmacology, Faculty of Pharmacy, Karadeniz Technical University, 61080, Trabzon, Türkiye.
Department of Pharmacology, Institute of Health Sciences, Karadeniz Technical University, 61080, Trabzon, Türkiye.
J Sex Med. 2024 Dec 1;21(12):1111-1119. doi: 10.1093/jsxmed/qdae129.
Diabetes mellitus-induced erectile dysfunction (DMED) is a common urological complication of diabetes, and current drugs often fail to provide an effective treatment. Smad2/3 signaling-mediated corporal fibrosis has a critical role in the molecular basis of DMED.
We investigated the effect of Niclosamide (Nic), an antihelmintic drug with antifibrotic effects, on erectile function in a rat DMED model.
Male Sprague Dawley rats were injected intraperitoneally (i.p) with streptozotocin (75 mg/kg) to induce diabetes. At week 8, both diabetic and nondiabetic rats were treated with Nic (10 mg·kg-1/day; i.p) or vehicle for 4 weeks. At week 12, erectile function was evaluated as intracavernous pressure (ICP) response to the electrical stimulation of the cavernous nerve (CN). Penile tissues were harvested for Masson's trichrome staining or western blotting to determine corporal fibrosis and Smad2/3 pathway-related protein expression, respectively.
At the end of the experimental protocol, in vivo erectile function was assessed by measuring the ratio of ICP/ mean arterial pressure (MAP) and total ICP following CN stimulation. Smooth muscle content and collagen fibers were evaluated by Masson's trichrome staining of the penile tissues. The expressions of fibrosis-related proteins (Smad2, Smad3, fibronectin) were determined using western blotting in the penile tissues.
Erectile function, as determined by the maximum ICP/MAP and total ICP/MAP ratios, was drastically decreased in diabetic rats. Corporal tissues of diabetic rats were severely fibrotic with a significant increase in collagen fibers and a marked reduction in smooth muscle content. Also, the protein expressions of phosphorylated (p-)Smad2, p-Smad3 and fibronectin were significantly increased in the penis of diabetic rats. Both functional and molecular alterations in DMED were effectively reversed by Nic-treated diabetic rats without a glycemic alteration.
Nic could be a promising candidate for the treatment of DMED due to its antifibrotic effects.
The present study provides the first evidence that Nic has beneficial effect on erectile dysfunction by attenuating corporal fibrosis in a rat model of DMED. The effect of Nic on penile endothelial function and the other potential underlying mechanisms needs to be further elucidated.
Nic improved erectile function in DMED rats possibly suppressing penile fibrosis by inhibiting Smad2/3 signaling. These results suggest a potential therapeutic repurposing of Nic as an adjuvant treatment in DMED.
糖尿病性勃起功能障碍（DMED）是糖尿病常见的泌尿系统并发症，目前的药物治疗往往效果不佳。Smad2/3信号介导的海绵体纤维化在DMED的分子机制中起关键作用。
我们研究了具有抗纤维化作用的抗蠕虫药氯硝柳胺（Nic）对大鼠DMED模型勃起功能的影响。
雄性Sprague Dawley大鼠腹腔注射链脲佐菌素（75 mg/kg）诱导糖尿病。第8周时，糖尿病大鼠和非糖尿病大鼠均接受Nic（10 mg·kg-1/天；腹腔注射）或溶剂处理4周。第12周时，通过海绵体内压（ICP）对海绵体神经（CN）电刺激的反应来评估勃起功能。采集阴茎组织进行Masson三色染色或蛋白质印迹分析，分别测定海绵体纤维化程度和Smad2/3信号通路相关蛋白的表达。
实验结束时，通过测量CN刺激后的ICP/平均动脉压（MAP）比值和总ICP来评估体内勃起功能。通过阴茎组织的Masson三色染色评估平滑肌含量和胶原纤维。使用蛋白质印迹法测定阴茎组织中纤维化相关蛋白（Smad2、Smad3、纤连蛋白）的表达。
糖尿病大鼠的勃起功能，通过最大ICP/MAP和总ICP/MAP比值测定，显著降低。糖尿病大鼠的海绵体组织严重纤维化，胶原纤维显著增加，平滑肌含量显著减少。此外，糖尿病大鼠阴茎中磷酸化（p-）Smad2、p-Smad3和纤连蛋白的蛋白表达显著增加。Nic治疗的糖尿病大鼠有效逆转了DMED的功能和分子改变，且血糖无变化。
由于其抗纤维化作用，Nic可能是治疗DMED的有前景的候选药物。
本研究首次证明Nic通过减轻大鼠DMED模型的海绵体纤维化对勃起功能障碍有有益作用。Nic对阴茎内皮功能的影响及其他潜在机制有待进一步阐明。
Nic改善了DMED大鼠的勃起功能，可能是通过抑制Smad2/3信号通路抑制阴茎纤维化。这些结果表明Nic作为DMED辅助治疗药物具有潜在的治疗用途。
