Sildenafil Enhances the Therapeutic Effect of Islet Transplantation for Diabetic Peripheral Neuropathy via mTOR/S6K1 Pathway

PURPOSE: This study aimed to investigate the potential mechanism underlying the therapeutic effect of sildenafil in combination with islet transplantation for diabetic peripheral neuropathy. METHODS: A streptozotocin-induced diabetic mouse model was established to evaluate the effects of islet transplantation and sildenafil intervention. The mice were subjected to different interventions for 6 weeks, and histopathological staining and immunohistochemistry techniques were employed to examine the pathological changes and protein expressions of BDNF, MBP, and cleaved caspase-3 in the sciatic nerve tissue. Moreover, RSC96 cells were cocultured with islet cells and sildenafil under high glucose conditions to investigate the potential involvement of the mTOR/S6K1 pathway, BDNF, and MBP proteins. Western blotting was used to detect protein expression in each group. RESULTS: The results showed that islet transplantation can restore sciatic nerve injury in diabetic mice, and sildenafil can enhance the therapeutic effect of islet transplantation. In addition, the combination of sildenafil and islet cells significantly upregulated the expression levels of mTOR/S6K1, BDNF, and MBP in RSC96 cells under high glucose conditions. CONCLUSIONS: Islet transplantation can reverse sciatic nerve injury in diabetic mice, and islet cells exhibit a protective effect on RSC96 cells under high glucose conditions via the activation of the mTOR/S6K1 pathway. Sildenafil enhances the therapeutic effect of islet transplantation, which may represent a potential treatment strategy for diabetic peripheral neuropathy.