title: Sequestration of brain derived nerve factor by intravenous delivery of TrkB-Ig2 reduces bladder overactivity and noxious input in animals with chronic cystitis.
abstract: Brain derived nerve factor (BDNF) is a trophic factor belonging to the neurotrophin family. It is upregulated in various inflammatory conditions, where it may contribute to altered pain states. In cystitis, little is known about the relevance of BDNF in bladder-generated noxious input and bladder overactivity, a matter we investigated in the present study. Female rats were intraperitoneally (i.p.) injected with cyclophosphamide (CYP; 200 mg/kg). They received saline or TrkB-Ig(2) via intravenously (i.v.) or intravesical administration. Three days after CYP-injection, animals were anaesthetized and cystometries performed. All animals were perfusion-fixed and the spinal cord segments L6 collected, post-fixed and processed for c-Fos and phosphoERK immunoreactivity. BDNF expression in the bladder, as well as bladder histology, was also assessed. Intravesical TrkB-Ig(2) did not change bladder reflex activity of CYP-injected rats. In CYP-animals treated with i.v. TrkB-Ig(2) a decrease in the frequency of bladder reflex contractions, in comparison with saline-treated animals, was observed. In spinal sections from the latter group of animals, the number of phosphoERK and c-Fos immunoreactive neurons was lower than in sections from saline-treated CYP-animals. BDNF immunoreactivity was higher during cystitis but was not changed by TrkB-Ig(2) i.v. treatment. Evaluation of the bladder histology showed similar inflammatory signs in the bladders of inflamed animals, irrespective of the treatment. Data show that i.v. but not intravesical administration of TrkB-Ig(2) reduced bladder hyperactivity in animals with cystitis to levels comparable to those observed in unirritated rats. Since i.v. TrkB-Ig(2) also reduced spinal extracellular signal-regulated kinase (ERK) activation, it is possible that BDNF contribution to inflammation-induced bladder hyperactivity is via spinal activation of the ERK pathway. Finally, the reduction in c-Fos expression indicates that TrkB-Ig(2) also reduced bladder-generated noxious input. Our results show that sequestration of BDNF may be considered a new therapeutic strategy to treat chronic cystitis.
authors.affiliation: Instituto de Biologia Celular e Molecular, Porto, Portugal; Department of Urology, Hospital de S João, Porto, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Pinto
authors.forename: B
authors.initials: B
authors.lastname: Frias
authors.forename: S
authors.initials: S
authors.lastname: Allen
authors.forename: D
authors.initials: D
authors.lastname: Dawbarn
authors.forename: S B
authors.initials: SB
authors.lastname: McMahon
authors.forename: F
authors.initials: F
authors.lastname: Cruz
authors.forename: C D
authors.initials: CD
authors.lastname: Cruz
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002908:Chronic Disease; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D007136:Immunoglobulins / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D010146:Pain / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012018:Reflex; D013116:Spinal Cord / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007136:Immunoglobulins; D016760:Proto-Oncogene Proteins c-fos; D011994:Recombinant Proteins; D003520:Cyclophosphamide; D020813:Receptor, trkB; D048049:Extracellular Signal-Regulated MAP Kinases