Intravesical Instillation with Vivo-Morpholino Nerve Growth Factor Antisense Therapy Ameliorates Acute Interstitial Cystitis/Painful Bladder Syndrome-Related Urinary Frequency in a Rat Model.

Abstract

INTRODUCTION AND HYPOTHESIS: Increased nerve growth factor (NGF) expression in the bladder is known to contribute to the hyperexcitability of C-fiber bladder afferent pathways in interstitial cystitis/painful bladder syndrome (IC/PBS). We hypothesized that intravesical administration of vivo-morpholino NGF antisense oligonucleotide (OND) would downregulate NGF expression and alleviate IC/PBS-associated urinary frequency. METHODS: Eighteen virgin female rats were randomly divided into three groups: (1) saline-injected control, (2) cyclophosphamide (CYP) plus intravesical instillation with normal saline, and (3) CYP plus intravesical instillation with vivo-morpholino NGF antisense OND (2 mg/kg). Female rats received an intravesical instillation of vivo-morpholino NGF antisense oligonucleotide once daily for three consecutive days, with a 30-min dwell time. Cystometric and histological evaluations were performed 24 h after the last instillation. Cystometry was used to evaluate voiding interval values under anesthesia, while NGF expression was measured. RESULTS: Immunohistochemistry demonstrated a ~ 26% increase in bladder NGF expression in CYP-induced IC/PBS rats compared with controls, particularly in the urothelium and suburothelium, whereas intravesical NGF antisense therapy reduced NGF levels by ~ 28%, approaching control values. Cystometric analysis revealed that CYP treatment reduced voiding intervals by ~ 61% at 24 h and ~ 40% at 48 h compared to controls, consistent with bladder overactivity. NGF antisense therapy markedly prolonged voiding intervals, increasing them by ~ 113% at 24 h and ~ 80% at 48 h compared with CYP, indicating progressive functional improvement. Baseline and maximal bladder pressures were not significantly different among groups. CONCLUSIONS: Intravesical administration of vivo-morpholino NGF antisense OND significantly prolonged voiding intervals and attenuated bladder NGF expression in CYP-induced acute IC/PBS female rats. These results highlight the potential of NGF antisense OND as a novel intravesical therapy for IC/PBS.