Effect of DPP-4 inhibitors on erectile dysfunction caused by vincristine in rats

Abstract

ABSTRACT Introduction Various chemotherapeutic agents are administered to cancer patients worldwide. Previously, an analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database showed that vincristine (VCR) increased the risk of erectile dysfunction (ED), as reported in the world meeting on Sexual Medicine 2018. As such, countermeasures for late complications after anticancer drug treatment are required. Neuropathy is a well-known side effect of VCR; however, in recent years, it has been reported that DPP-4 inhibitors improve neuropathy. Objective To investigate the effect of DPP-4 inhibitors to ED caused by VCR in rats. Methods Twelve-week-old male Wistar ST rats were separated into Control, VCR, and VCR+DPP-4i groups. VCR (0.1 mg/kg) was intravenously administered on days 1, 8, 15, and 22 in the VCR and VCR+DPP-4i groups. Two types of long-term preparations, toleragliptin (TGP; 3 mg/kg/week, po.) and omaligliptin (OGP; 3 mg/kg/week, po.), were examined for DPP-4i. Erectile function was tested using intracavernous pharmacotherapy (ICP) measurements, and endothelial function was tested through an isometric tension study. Additionally, mRNA expressions were tested using real-time PCR. Results After the 4-week observation period, the ICP/mean arterial pressure (MAP) ratio in the VCR group (0.42 ± 0.04) was significantly decreased compared to the Control group (0.72 ± 0.05) (P <0.01). The ICP/MAP ratio in the VCR+TGP group (0.64 ± 0.02) increased significantly compared to the VCR group (P <0.05), however the ICP/MAP ratio in the VCR+OGP (0.50 ± 0.08) did not increase significantly compared to the VCR group (P > 0.05). Real-time PCR analysis showed that the catalase, VEGF, MCP-1, and PAI-1 mRNA expressions were increased, while the IL-6 mRNA expression decreased significantly in the VCR+TGP and VCR+OGP groups. In contrast, the nNOS mRNA expression level was higher in the VCR+TGP group than in the VCR+OGP group. Conclusions In this study, we determined that DPP-4 inhibitors may improve ED by VCR administration. For ED associated with VCR administration, long-term DPP-4 inhibitor TGP administration suggested a significant improvement in erectile function, but OGP did not show a significant improvement effect. An increase in antioxidant activity and a decrease in inflammatory cytokines were observed for both drugs, including a surge in vascular increase factors. In contrast, the nNOS expression level was higher in TGP, suggesting that there may be a difference in the amount of NO production via nerves. Therefore, TGP may be useful for male sexual dysfunction associated with vincristine administration. Disclosure Work supported by industry: no.