Introduction

Increased afferent excitability is considered to be an important pathophysiological basis of interstitial cystitis/bladder pain syndrome (IC/BPS) and overactive bladder (OAB). Also, transient receptor potential vanilloid 1 (TRPV1) receptors are known to be involved in afferent sensitization. Therefore, we investigated the effect of gene therapy with HSV vectors encoding PL or PP1α, a negative regulator of TRPV1, using a rat model of long-lasting cystitis induced by hydrogen peroxide (HP).

Methods

HSV vectors encoding green fluorescent protein (GFP), PL or PP1α were injected into the bladder wall of female SD rats. One week later, 1% HP or normal saline (NS) was administered into the bladder. Awake cystometry (CMG), resiniferatoxin (RTX)-induced nociceptive behaviors such as licking and freezing, NGF mRNA expression in the bladder, bladder weight and histology were evaluated 2 weeks after viral injection.

Results

In CMG, the GFP/HP group showed a significant decrease in intercontraction intervals compared to the GFP/NS group, which were significantly prolonged by 57.8% and 68.0% in PL/HP and PP1α/HP groups (p<0.01), respectively. The number of freezing behavior was significantly lower in PL/HP and PP1α/HP groups by 86.1% and 93.5%, respectively, compared to the GFP/HP group. Compared with the GFP/NS group, the GFP/HP group had significantly heavier bladder weight, whereas the PL/HP group and PP1α/HP group showed significantly lighter bladder weight than the GFP/HP group. Hematoxylin and eosin staining of bladder sections showed substantial inflammation characterized by inflammatory cell infiltration, and detrusor hypertrophy in the bladder in the GFP/HP group compared with GFP/NS group, which were alleviated in PL/HP and PP1α/HP groups. In RT-PCR, the GFP/HP group showed higher significantly (p<0.05) expression of NGF mRNA in the bladder mucosa than the GFP/NS group, which was significantly decreased in the PL/HP and PP1α/HP groups (p < 0.05).

Conclusions

HSV vectors-mediated gene delivery of PL or PP1α significantly reduced bladder overactivity and enhanced bladder pain sensitivity in HP cystitis rats. Also, both treatments can reduce bladder inflammatory changes and increased bladder weight at least in part through amelioration of NGF overexpression in the bladder mucosa. Thus, HSV-mediated TRPV1-targeting gene therapy could be effective for the treatment of IC/BPS including Hunner-type IC that is often associated with bladder inflammation.

Funding

DOD W81XWH-12-1-0565; NIH DK088836