普罗布考通过激活 Nrf2 改善糖尿病大鼠的勃起功能，并协调 HO-1/DDAH/PPAR-γ/eNOS 通路。
Probucol improves erectile function via Activation of Nrf2 and coordinates the HO-1 / DDAH / PPAR-γ/ eNOS pathways in streptozotocin-induced diabetic rats.
机构信息
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, People's Republic of China; Department of Urology, Shandong Zaozhuang Municipal Hospital, Zaozhuang, 277000, People's Republic of China.
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, People's Republic of China.
出版信息
Biochem Biophys Res Commun. 2018 Dec 9;507(1-4):9-14. doi: 10.1016/j.bbrc.2018.10.036. Epub 2018 Nov 16.
BACKGROUND
Diabetic erectile dysfunction (DMED) is mainly attributed to oxidative stress, and Nrf2 plays an important role in cellular antioxidation and regulates NO production in the vascular endothelium. Probucol maintains endothelial function through its antioxidant activity. This study investigated the efficacy and mechanism of probucol in improving erectile function in streptozotocin-induced diabetic rats.
METHODS
In our study, thirty 12-week-old Sprague-Dawley male rats were fasted for 12 h. All rats received a 1-time injection of intraperitoneal streptozotocin(60 mg/kg) or vehicle. After 72 h, STZ-treated rats (with random blood glucose concentrations consistently greater than 16.7 mmol/L) were considered diabetic. The diabetic rats were randomly assigned into 2 groups and treated with daily gavage feedings of probucol at doses of 0 and 500 mg/kg for 12 weeks. A positive control group underwent intraperitoneal injection of normal saline followed by daily gavage of saline solution. Erectile function was assessed by electrical stimulation of the cavernous nerves with real-time intracavernous pressure measurement. After euthanasia, penile tissue was investigated using immunohistochemistry, Western blot, and ELISA to assess the proteins of Nrf2/HO-1/DDAH/PPAR-γ/eNOS pathways.
RESULTS
After treatment, the rats in the probucol group presented significantly improved erectile function (P < 0.05) than that of the diabetic group without probucol treatment (DM). Also, protein expression of Nrf2, DDAH, PPAR-γ, HO-1 and eNOS was significantly higher than that of the DM group (P < 0.05). CGMP concentrations and SOD concentrations of probucol-treated rats were higher than those of DM group (P < 0.05). The MDA levels and ADMA levels were significantly lower than those of DM group rats (P < 0.05).
CONCLUSION
Probucol can improve erectile function via activation of Nrf2, which coordinates the HO-1/DDAH/PPAR-γ/eNOS pathways in streptozotocin-induced diabetic rats.
背景
糖尿病性勃起功能障碍（DMED）主要归因于氧化应激，而 Nrf2 在细胞抗氧化和调节血管内皮中 NO 产生方面起着重要作用。普罗布考通过其抗氧化活性维持内皮功能。本研究旨在探讨普罗布考改善链脲佐菌素诱导的糖尿病大鼠勃起功能的疗效和机制。
方法
在我们的研究中，30 只 12 周龄的 Sprague-Dawley 雄性大鼠禁食 12 小时。所有大鼠均接受单次腹腔注射链脲佐菌素（60mg/kg）或载体。72 小时后，STZ 处理的大鼠（随机血糖浓度持续大于 16.7mmol/L）被认为患有糖尿病。糖尿病大鼠随机分为 2 组，分别给予 0 和 500mg/kg 普罗布考每日灌胃 12 周。阳性对照组接受腹腔注射生理盐水，随后每日灌胃生理盐水。通过实时海绵体内压测量对海绵体神经进行电刺激评估勃起功能。安乐死后，通过免疫组织化学、Western blot 和 ELISA 检测评估 Nrf2/HO-1/DDAH/PPAR-γ/eNOS 通路的蛋白，研究阴茎组织。
结果
治疗后，普罗布考组大鼠的勃起功能明显改善（P<0.05），优于未用普罗布考治疗的糖尿病组（DM）。此外，Nrf2、DDAH、PPAR-γ、HO-1 和 eNOS 的蛋白表达均明显高于 DM 组（P<0.05）。普罗布考治疗组大鼠 cGMP 浓度和 SOD 浓度均高于 DM 组（P<0.05）。MDA 水平和 ADMA 水平明显低于 DM 组大鼠（P<0.05）。
结论
普罗布考可通过激活 Nrf2 改善链脲佐菌素诱导的糖尿病大鼠的勃起功能，该作用通过协调 HO-1/DDAH/PPAR-γ/eNOS 通路来实现。
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