MP43-06: Inhibition of proNGF pathway restores erectile f ... c and neurotrophic effects in the diabetic mouse

Inhibition of proNGF pathway restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse

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INTRODUCTION

Patients with diabetic erectile dysfunction (ED) usually respond poorly to oral PDE5 inhibitors due to a lack of bioavailable nitric oxide from severe endothelial and neural dysfunction. ProNGF and its receptor p75NTR are known to be up-regulated in diabetic condition and to induce endothelial cell apoptosis and neuronal degeneration. The aim of this study was to investigate effectiveness of anti-proNGF neutralizing antibody (proNGF-Ab) in restoring erectile function in streptozotocin-induced diabetic mouse.

METHODS

Diabetes was induced by intraperitoneal injection of streptozotocin (50 mg/kg) into 8-week-old C57BL/6 male mice for 5 consecutive days. At 8 weeks after the induction of diabetes, the animals were distributed into 3 groups: controls, streptozotocin-induced diabetic mice receiving repeated intracavernous injections of PBS (days -3 and 0; 20 µL) or proNGF-Ab (days -3 and 0; 20 µg in 20 µL of PBS). We measured erectile function by electrical stimulation of the cavernous nerve at 2 weeks after treatment. The penis was harvested and stained with antibodies to proNGF, CD31, VE-cadherin, and βIII-tubulin. We also performed TUNEL assay and Western blot analysis for p75NTR.

RESULTS

The cavernous expression of proNGF and p75NTR was up-regulated in diabetic mice. Local delivery of proNGF-Ab into the corpus cavernosum of diabetic mice was effective to neutralize proNGF and profoundly down-regulated expression of p75NTR. Intracavernous injection of proNGF-Ab induced significant restoration of erectile function in diabetic mice, which reach up to 90-100% of control values. ProNGF-Ab significantly increased cavernous endothelial cell content and endothelial cell-cell junction proteins; decreased endothelial cell apoptosis; and restored neuronal cell content in the cavernous tissue of diabetic mice.

CONCLUSION

Our findings suggest that inhibition of proNGF pathway is a promising therapeutic strategy for diabetic ED.

Funding: This research was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Ji-Kan Ryu, HI15C0508) and The National Research Foundation of Korea(NRF) funded by the Ministry of Education (Kang-Moon Song, 2017R1A6A3A11030261).