Premium
Use of a Non‐Native Chloride Channel as a Treatment for Interstitial Cystitis
Author(s) -
Beckel Jonathan M,
Tillman Tommy S,
Tang Pei,
Groat William C,
Xu Yan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.720.6
Subject(s) - cystometry , interstitial cystitis , urinary bladder , medicine , urothelium , inflammation , visceral pain , nociception , urology , urinary system , pharmacology , receptor
Interstitial cystitis (IC) is a disease of the urinary bladder that causes increased urgency to void and pelvic pain. It is commonly thought that increased bladder sensations in IC are due to sensitization of bladder afferent nerves by inflammatory mediators. Current therapies aimed at known targets in the inflammatory or nociceptive pathways have, to date, been ineffective at reducing the symptoms in IC patients. To find potential new treatments for IC, we expressed a non‐native chloride channel (EG3RF) in bladder afferent neurons. This family of channels can be activated by either inflammatory conditions or by an exogenous pharmaceutical compound, but has no activity under normal physiological conditions. We hypothesize that successful transfection of the EG3RF chloride channel into rat bladder afferent nerves will diminish bladder hyperexcitability in the cyclophosphamide model of bladder inflammation. To transfect bladder afferent nerves, an expression plasmid containing the sequence for EG3RF was encapsulated in liposomes and instilled into the urinary bladder of Sprague Dawley rats using a transurethral catheter. Bladder activity was measured 1–2 weeks later using metabolic cages or bladder cystometry. Bladder inflammation was induced by intraperitoneal injection of cyclophosphamide (CYP, 150 mg/kg) 1 hour prior to measurement of bladder activity. Successful expression of the EG3RF channel up to 2 weeks following transfections was confirmed in the bladder smooth muscle, urothelium and dorsal root ganglia (T11–12, L1–L2 and L6‐S1 levels) using RT‐PCR, Western blot, and immunofluorescence analyses. Metabolic cage and cystometry experiments indicated no differences in voiding function between the control and non‐inflamed EG3RF‐transfected animals. However, EG3RF‐transfected rats were resistant to the excitatory effects of cyclophosphamide treatment. Treatment with cysteamine, which has been shown to activate EG3RF, decreased CYP‐induced bladder activity in both metabolic cage and cystometry experiments (31 mg/kg ip or iv, respectively) in EG3RF‐transfected rats but was ineffective in control rats. Intravesical instillation of cysteamine (5 mM) during cystometry in EG3RF‐transfected rats excited bladder reflexes while iv administration (31 mg/kg) decreased peak micturition pressure. These data suggest that expression of a non‐native chloride channel in bladder afferent nerves may be an effective treatment for painful bladder disorders such as interstitial cystitis. Further development of the technique may lead to significant advances in efficacy over existing treatments. Support or Funding Information T32 GM075770 (Xu); K01 DK106115 (Beckel); R01 DK091253 (de Groat)