Role of p75NTR in female rat urinary bladder with cyclophosphamide-induced cystitis.
Previous studies demonstrated changes in urinary bladder neurotrophin content and upregulation of neurotrophin receptors, TrkA and the p75 neurotrophin receptor (p75(NTR)), in micturition reflex pathways after cyclophosphamide (CYP)-induced cystitis. p75(NTR) can bind nerve growth factor (NGF) and modulate NGF-TrkA binding and signaling. We examined p75(NTR) expression and the role of p75(NTR) in the micturition reflex in control and CYP-treated rats. p75(NTR) Immunoreactivity was present throughout the urinary bladder. CYP-induced cystitis (4 h, 48 h, chronic) increased (P < or = 0.05) p75(NTR) expression in whole urinary bladder as shown by Western blotting. The role of p75(NTR) in bladder function in control and CYP-treated rats was determined using conscious cystometry and immunoneutralization or PD90780, a compound known to specifically block NGF binding to p75(NTR). An anti-p75(NTR) monoclonal antibody or PD90780 was infused intravesically and cystometric parameters were evaluated. Both methods of p75(NTR) blockade significantly (P < or = 0.05) decreased the intercontraction interval and void volume in control and CYP-treated rats. Intravesical infusion of PD90780 also significantly (P < or = 0.001) increased intravesical pressure and increased the number of nonvoiding contractions during the filling phase. Control intravesical infusions of isotype-matched IgG and vehicle were without effect. Intravesical instillation of PD90780 significantly (P < or = 0.01) reduced the volume threshold to elicit a micturition contraction in control rats (no inflammation) and CYP-treated in a closed urinary bladder system. These studies demonstrate 1) ubiquitous p75(NTR) expression in urinary bladder and increased expression with CYP-induced cystitis and 2) p75(NTR) blockade at the level of the urinary bladder produces bladder hyperreflexia in control and CYP-treated rats. The overall activity of the urinary bladder reflects the balance of NGF-p75(NTR) and NGF-TrkA signaling.
Dept. of Neurology, Univ. of Vermont College of Medicine, D415A Given Research Bldg., Burlington, VT 05405, USA.
Mary Beth
MB
Klinger
Margaret A
MA
Vizzard
D000818:Animals; D003520:Cyclophosphamide / Q000633:toxicity*; D003556:Cystitis / Q000139:chemically induced* / Q000503:physiopathology*; D005260:Female; D009419:Nerve Tissue Proteins; D011479:Protamines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D001743:Urinary Bladder / Q000187:drug effects / Q000503:physiopathology*
D009419:Nerve Tissue Proteins; C096822:PD 90780; D011479:Protamines; D011799:Quinazolines; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C068313:Ngfr protein, rat; D003520:Cyclophosphamide