S-Nitrosoglutathione protects the spinal bladder: novel therapeutic approach to post-spinal cord injury bladder remodeling.
OBJECTIVE
Bladder and renal dysfunction are secondary events of the inflammatory processes induced by spinal cord injury (SCI). S-Nitrosoglutathione (GSNO), an endogenous nitrosylating agent is pleiotropic and has anti-inflammatory property. Hence, GSNO ameliorates inflammatory sequelae observed in bladder and renal tissues after SCI. Thus, we postulate that GSNO will improve the recovery of micturition dysfunction by quenching the bladder tissue inflammation associated with SCI.


METHODS
Contusion-based mild SCI was induced in female Sprague-Dawley rats. Sham operated rats served as the controls. SCI rats were gavaged daily with GSNO (50 µg/kg) or vehicle. Bladder function was assessed by urodynamics at 2 and 14 days following SCI. Urine protein concentration and osmolality were measured. Bladder and kidney tissues were analyzed by histology and immunofluorescence for a variety of endpoints related to inflammation.


RESULTS
Two days after SCI, urodynamics demonstrated a hyperreflexive bladder with overflow and no clear micturition events. By Day 14, vehicle animals regained a semblance of a voiding cycle but with no definite intercontraction intervals. GSNO-treated SCI-rats showed nearly normal cystometrograms. Vehicle-treated SCI rats had increased bladder wet weight, proteinuria, and urine osmolality at Day 14, which was reversed by GSNO treatment. In addition, the SCI-induced increase in immune cell infiltration, collagen deposition, iNOS, and ICAM-1 expression and apoptosis were attenuated by GSNO.


CONCLUSIONS
These results indicate that oral administration of GSNO hastens the recovery of bladder function after mild contusion-induced SCI through dampening the inflammation sequelae. These findings also suggest that GSNO-mediated redox modulation may be a novel therapeutic target for the treatment of mild SCI-induced renal and bladder dysfunction.
Department of Pediatrics, Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina.
Anandakumar
A
Shunmugavel
Department of Pediatrics, Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina.
Mushfiquddin
M
Khan
Department of Urology, Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina.
Francis M
FM
Hughes
Department of Urology, Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina.|Department of Regenerative Medicine and Cell Biology, Pathology and Laboratory Medicine Service, Medical University of South Carolina, Charleston, South Carolina.
J Todd
JT
Purves
Ralph H. Johnson Veterans Administration Medical Center, Pathology and Laboratory Medicine Service, Medical University of South Carolina, Charleston, South Carolina.
Avtar
A
Singh
Department of Pediatrics, Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina.
Inderjit
I
Singh
D000818:Animals; D003288:Contusions / Q000150:complications; D003556:Cystitis / Q000188:drug therapy / Q000209:etiology; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009929:Organ Size; D011507:Proteinuria / Q000188:drug therapy / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026422:S-Nitrosoglutathione / Q000627:therapeutic use*; D013119:Spinal Cord Injuries / Q000150:complications*; D001743:Urinary Bladder / Q000473:pathology; D001745:Urinary Bladder Diseases / Q000473:pathology / Q000517:prevention & control*; D014555:Urination Disorders / Q000188:drug therapy / Q000209:etiology; D014563:Urodynamics
D018799:Intercellular Adhesion Molecule-1; D026422:S-Nitrosoglutathione; D052247:Nitric Oxide Synthase Type II
GSNO; ICAM-1; bladder dysfunction; iNOS; inflammation; spinal cord injury