Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Second Clinical College, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Redox Biol. 2023 Dec;68:102938. doi: 10.1016/j.redox.2023.102938. Epub 2023 Oct 18.
To investigate the therapeutic potential of dimethyl fumarate (DMF) in improving erectile function of bilateral cavernous nerve injury (BCNI) rats, along with elucidating its underlying mechanisms.
A BCNI rat model was established by clamping bilateral cavernous nerve (CN). DMF was given by gavage at low (20 mg/kg/day) and high (40 mg/kg/day) dosages for a duration of 4 weeks. Erectile function was assessed by electrical stimulation of CN. Penis and CN tissues were collected for subsequent analysis. Additionally, PC-12 cell line was used to verify the mechanism of DMF in vitro. Nfe2l2 or Ho-1 gene knockdown PC-12 cell lines were constructed by lentiviral transfection, respectively. A damaged cell model was induced using HO. And then molecular biological methods were employed to analyze cellular molecules and proteins.
DMF administration for 4 weeks led to improvements in erectile function, reduced fibrosis of penis corpus cavernosum in BCNI rats. The morphology of CN was improved and the number of nerve fibers increased. Furthermore, the levels of nNOS, NO, and cGMP were increased, while Ca was decreased in penis corpus cavernosum. Notably, the levels of ROS, 3-NT and NLRP3 inflammasomes production were reduced, alongside increased expression of Nrf2 and HO-1 proteins in the dorsal penile nerve (DPN) and CN. In vitro, DMF increased cell viability, reduced ROS level, promoted SOD, diminished 3-NT, MDA and DNA damage markers, and inhibited the activation of NLRP3 inflammasomes in HO induced PC-12 cells. Nfe2l2 knockdown and Ho-1 knockdown significantly attenuated the protective effect of DMF, respectively. Furthermore, inhibition of ROS production by N-acetylcysteine led to a reduction in NLRP3 inflammasome activation in HO induced PC-12 cells.
DMF improved erectile function of BCNI rats by protecting nerves through inhibiting oxidative stress and the activation of NLRP3 inflammasome-mediated pyroptosis via activation of Nrf2/HO-1 pathway.
探讨二甲基富马酸（DMF）改善双侧海绵体神经损伤（BCNI）大鼠勃起功能的治疗潜力，并阐明其潜在机制。
采用夹闭双侧海绵体神经（CN）的方法建立 BCNI 大鼠模型。DMF 灌胃给药，低（20mg/kg/天）和高（40mg/kg/天）剂量组给药 4 周。通过 CN 电刺激评估勃起功能。采集阴茎和 CN 组织进行后续分析。此外，还使用 PC-12 细胞系在体外验证 DMF 的作用机制。通过慢病毒转染分别构建 Nfe2l2 或 Ho-1 基因敲低 PC-12 细胞系。用 HO 诱导构建损伤细胞模型，然后采用分子生物学方法分析细胞分子和蛋白。
DMF 给药 4 周可改善勃起功能，减少 BCNI 大鼠阴茎海绵体纤维化。CN 形态得到改善，神经纤维数量增加。此外，阴茎海绵体中 nNOS、NO 和 cGMP 水平升高，Ca 水平降低。值得注意的是，ROS、3-NT 和 NLRP3 炎性小体产物水平降低，DPN 和 CN 中 Nrf2 和 HO-1 蛋白表达增加。体外，DMF 增加细胞活力，降低 ROS 水平，促进 SOD，减少 3-NT、MDA 和 DNA 损伤标志物，抑制 HO 诱导的 PC-12 细胞中 NLRP3 炎性小体的激活。Nfe2l2 敲低和 Ho-1 敲低分别显著减弱了 DMF 的保护作用。此外，ROS 生成抑制剂 N-乙酰半胱氨酸可减少 HO 诱导的 PC-12 细胞中 NLRP3 炎性小体的激活。
DMF 通过抑制氧化应激和激活 Nrf2/HO-1 通路抑制 NLRP3 炎性小体介导的细胞焦亡来保护神经，从而改善 BCNI 大鼠的勃起功能。
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