Roles of nerve growth factor in bladder storage dysfunction due to detrusor overactivity in spinal cord injured mice – analysis of time-dependent responses
Sources of Funding: NIH P01 DK093424
Introduction
We previously reported the urodynamic effect of 1-week anti-nerve growth factor (NGF) treatment in mice with spinal cord injury (SCI), but failed to show the reduction in NGF expression in the bladder (2016 AUA). Therefore, we investigated the time-dependency of the efficacy of anti-NGF treatment in SCI mice.
Methods
SCI was induced by Th8/9 spinal cord transection in female C57BL/6N mice. SCI mice were divided into 3 groups. Group A did not receive any treatments. Groups B and C respectively received 1-week and 2-weeks anti-NGF antibody treatments (10µg/kg/hr) using an osmotic pump placed subcutaneously before the final evaluation. Four weeks after SCI, animals were evaluated using single-filling cystometry under an awaken condition. NGF levels in the bladder and spinal cord were measured, and the mRNA expression of P2X2, P2X3, TRPA1 and TRPV1 was also evaluated in L6/S1 dorsal root ganglia (DRG).
Results
There were no significant differences in micturition pressure, threshold pressure, voided volume, post-void residual, bladder capacity or voiding efficiency among 3 groups. The number of non-voiding contractions (NVCs) per a voiding cycle in groups B and C were significantly lower than that of group A. NGF levels of the bladder mucosa and spinal cord of SCI mice (group A) were significantly increased compared with spinal intact mice. Two-weeks (group C), but not one-week (group B), anti-NGF treatment significantly decreased bladder mucosal and spinal NGF expression. The mRNA levels of TRPA1 and TRPV1 were increased in SCI mice compared to spinal intact mice, and significantly decreased after both 1 week and 2 weeks of anti-NGF treatment.
Conclusions
One-week and 2-week treatments similarly improved NVCs in association with the reduction of the expression of TRPA1 and TRPV1 in L6/S1 DRG although 2-weeks anti-NGF treatment was required to significantly decrease bladder mucosal and spinal NGF. Thus, NGF overexpression is likely to play a significant role in storage dysfunction to induce DO in SCI mice.
Funding
NIH P01 DK093424
Takahiro Shimizu
Nobutaka Shimizu
Pradeep Tyagi
William de Groat
Anthony Kanai
Hidehiro Kakizaki
Naoki Yoshimura