Baicalein Alleviates Erectile Dysfunction Associated with Streptozotocin-Induced Type I Diabetes by Ameliorating Endothelial Nitric Oxide Synthase Dysfunction, Inhibiting Oxidative Stress and Fibrosis

Abstract

Background Management of diabetes mellitus induced-erectile dysfunction (DMED) is challenging because of its poor responses to phosphodiesterase type 5 inhibitors. Increasingly important roles of 12-lipoxygenase (12-LOX) have been proven in diabetes mellitus. Aim To investigate 12-LOX activity and therapeutic effect of its inhibitor, baicalein (BE), on DMED. Methods Intraperitoneal streptozotocin injection was used to induce type I DM, and an apomorphine test was used to evaluate erectile function. In experiment A, we assessed 12-LOX expression alteration in the corpus cavernosum (CC) of rats with DMED of different levels of severity. In experiment B, rats with DMED were intraperitoneally injected with BE for 4 weeks, and control rats were injected with vehicles. The erectile function was tested by cavernous nerve stimulation before penile tissue was harvested. We performed Western blot, immunohistochemistry, immunofluorescence, Masson trichrome staining, and enzyme-linked immunosorbent assays to measure related proteins in CC. Main Outcome Measure The main outcome measures included rectile response, histologic examination, and expression alteration of related proteins. Results 12-LOX upregulation was associated with the progression of type I DMED. After 4 weeks treatment, compared with the DMED group, the DMED + BE group showed better erectile responses to cavernous nerve stimulation. In the DMED + BE group, significantly enhanced endothelial nitric oxide synthase/nitric oxide/cyclic guanosine monophosphate pathway, reduced 12-LOX expression, and inhibited p38 mitogen-activated protein kinase/arginase II/L-arginine pathway were showed in CC relative to the DMED group. In addition, overactivated oxidative stress and fibrosis in the DMED group were both partially ameliorated in the DMED + BE group. Clinical Implications BE may be considered as an effective therapy for DMED, but needs to be verified in future human investigations. Strengths & Limitations The role of 12-LOX and its inhibitor, BE, is firstly demonstrated in rats with type I DMED. However, the experimental data are derived from animal models with without evidences from cellular-based experiments. Conclusion 12-LOX might serve as an important factor in the pathogenesis of type I DMED. BE alleviated erectile dysfunction in rats with type I DMED probably by inhibiting 12-LOX expression, ameliorating endothelial nitric oxide synthase dysfunction, as well as suppressing oxidative stress and fibrosis.

Berberine ameliorates erectile dysfunction in rats with streptozotocin‐induced diabetes mellitus through the attenuation of apoptosis by inhibiting the SPHK1/S1P/S1PR2 and MAPK pathways

“…47 According to previous studies, apoptosis in the CC of diabetic rats was obviously excessive, and inhibiting apoptosis was an effective way to restore the erectile function of diabetic rats. 19,20 induced diabetic rats and HG-induced nephropathy. 48,49 In this study, BBR treatment reduced the expression of proapoptotic molecules and inhibited excessive apoptosis in the CC of diabetic rats.…”

“…Studies have shown that when DNA is damaged, increased ERK1/2 can interact with p53 and promote p53 phosphorylation, which may be one of the mechanisms that induces apoptosis 47 . According to previous studies, apoptosis in the CC of diabetic rats was obviously excessive, and inhibiting apoptosis was an effective way to restore the erectile function of diabetic rats 19,20 . Zhu et al.…”

“…Previous studies have shown the potential of Chinese herbal medicine in improving erectile function in DM rats. 20,28 As a commonly used herbal extract, BBR has previously been reported to have anti-inflammatory, antioxidant, and antiapoptotic effects on diabetes and its complications. 29 These biological effects may also be essential for the treatment of DMED, which is a common complication of DM.…”

“…The other eight rats were injected with vehicle (0.1 mol/L citrate phosphate buffer; pH 4.2) 19 . Fasting glucose was measured, and after 72 h, 39 rats with DM (fasting glucose > 16.7 mmol/L) were selected for the follow‐up experiment 20 …”

“…A total of 50 male Sprague-Dawley (SD) rats ( 19 Fasting glucose was measured, and after 72 h, 39 rats with DM (fasting glucose > 16.7 mmol/L) were selected for the follow-up experiment. 20 Thirty-five rats with DM survived (4 rats died because of uncontrollable blood glucose changes) and underwent the apomorphine (APO) test (80 μg/kg, 40 μg/ml in normal saline with vitamin C 0.1 g/L, Sigma-Aldrich) after 8 weeks of meticulous feeding. 21 Then, 16 APOnegative rats (considered the DMED model) were randomly used in the two experimental groups (eight per group).…”