title: Inosine Improves Neurogenic Detrusor Overactivity following Spinal Cord Injury.
abstract: Neurogenic detrusor overactivity and the associated loss of bladder control are among the most challenging complications of spinal cord injury (SCI). Anticholinergic agents are the mainstay for medical treatment of detrusor overactivity. However, their use is limited by significant side effects such that a search for new treatments is warranted. Inosine is a naturally occurring purine nucleoside with neuroprotective, neurotrophic and antioxidant effects that is known to improve motor function in preclinical models of SCI. However, its effect on lower urinary tract function has not been determined. The objectives of this study were to determine the effect of systemic administration of inosine on voiding function following SCI and to delineate potential mechanisms of action. Sprague-Dawley rats underwent complete spinal cord transection, or cord compression by application of an aneurysm clip at T8 for 30 sec. Inosine (225 mg/kg) or vehicle was administered daily via intraperitoneal injection either immediately after injury or after a delay of 8 wk. At the end of treatment, voiding behavior was assessed by cystometry. Levels of synaptophysin (SYP), neurofilament 200 (NF200) and TRPV1 in bladder tissues were measured by immunofluorescence imaging. Inosine administration decreased overactivity in both SCI models, with a significant decrease in the frequency of spontaneous non-voiding contractions during filling, compared to vehicle-treated SCI rats (p<0.05), including under conditions of delayed treatment. Immunofluorescence staining demonstrated increased levels of the pan-neuronal marker SYP and the Adelta fiber marker NF200, but decreased staining for the C-fiber marker, TRPV1 in bladder tissues from inosine-treated rats compared to those from vehicle-treated animals, including after delayed treatment. These findings demonstrate that inosine prevents the development of detrusor overactivity and attenuates existing overactivity following SCI, and may achieve its effects through modulation of sensory neurotransmission.
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts, United States of America; Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Yeun Goo
authors.initials: YG
authors.lastname: Chung
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts, United States of America; Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Seth
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts, United States of America; Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Claire
authors.initials: C
authors.lastname: Doyle
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Debra
authors.initials: D
authors.lastname: Franck
authors.affiliation: Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Urology, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America; Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Vivian
authors.initials: V
authors.lastname: Cristofaro
authors.affiliation: Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Larry I
authors.initials: LI
authors.lastname: Benowitz
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts, United States of America; Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Duong D
authors.initials: DD
authors.lastname: Tu
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts, United States of America; Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Estrada
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts, United States of America; Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Mauney
authors.affiliation: Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Urology, VA Boston Healthcare System, West Roxbury, Massachusetts, United States of America; Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Maryrose P
authors.initials: MP
authors.lastname: Sullivan
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital, Boston, Massachusetts, United States of America; Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Adam
mesh_terms: D000818:Animals; D007288:Inosine / Q000494:pharmacology*; D008297:Male; D016900:Neurofilament Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016708:Synaptophysin / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D016900:Neurofilament Proteins; D016708:Synaptophysin; C569016:Syp protein, rat; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C051774:neurofilament protein H; D007288:Inosine