OnabotulinumtoxinA intradetrusorial injections modulates bladder expression of NGF, TrkA, p75 and TRPV1 in patients with detrusor overactivity

OnabotulinumtoxinA (BoNT/A) intradetrusorially injected in patients with neurogenic and idiopathic detrusor overactivity (DO) significantly decreased NGF levels and TRPV1 expression in bladder and urine. To date no information exist on gene expression of TrkA and p75 (NGF receptors) in bladder tissues of patients treated with BoNT/A. In this study we investigated BoNT/A-induced changes in gene expression of TRKA and p75, and of NGF and TRPV1 in bladder tissue of patients with neurogenic and idiopathic DO. MATERIAL & METHODS: 18 patients with neurogenic DO and 7 with idiopathic DO underwent clinical, urodynamic and cystoscopic evaluation with bladder biopsy specimen before (T0) and one month (T1) after intradetrusor BoNT/A injection (300 U in neurogenic DO and 100 U in idiopathic DO). Changes in gene expression of NGF, TRPV1, TRKA and p75 were investigated with Real Time PCR (qPCR) at T0 and T1. Changes in NGF-protein content (ng/mg) were measured by ELISA assay at T0 and T1. Data are expressed as post/pre ratio. RESULTS: Clinical and urodynamic significant improvements were observed in all patients at T1. We observed a significant increase in NGF (1.68±0.2 folds), TRPV1 (1.83±0.3 folds), TRKA (1.36±0.2 folds) and p75 (2.02±0.4 folds) expression in all patients and a significant decrease in NGF protein bladder content (689±113 ng/total mg vs. 252±67 ng/total mg). (Fig. 1) We found a linear correlation between changes in NGF and TRKA (p=0.005), NGF and TRPV1 (p=0.02), TRKA and TRPV1 (p=0.0002). Patients injected with 300 BoNT/A U had a higher increase in NGF, TRPV1 and TRKA expression than those who received 100 U. No significant correlation was found between p75 and changes in NGF expression (p=0.17). CONCLUSIONS: We confirm the previously reported activity of BoNT/A in reducing NGF bladder tissue content in patients with neurogenic and idiopathic DO. The novel finding of this study was the significant neurotoxin- induced up-regulation of bladder NGF, TrkA and TRPV1 in the short time. This may represent a compensatory change aimed at re-establishing NGF bladder levels and activity. The linear correlation existing among NGF, TrkA and TRPV1 overexpression after treatment demonstrated a strictly linked activity of these transmitters/receptors. p75 expression was highly variable and reflected the fact it is a "pan-neuroreceptor".