Up-regulation of brain-derived neurotrophic factor in primary afferent pathway regulates colon-to-bladder cross-sensitization in rat

Background In humans, inflammation of either the urinary bladder or the distal colon often results in sensory cross-sensitization between these organs. Limited information is known about the mechanisms underlying this clinical syndrome. Studies with animal models have demonstrated that activation of primary afferent pathways may have a role in mediating viscero-visceral cross-organ sensitization. Methods Colonic inflammation was induced by a single dose of tri-nitrobenzene sulfonic acid (TNBS) instilled intracolonically. The histology of the colon and the urinary bladder was examined by hematoxylin and eosin (H&E) stain. The protein expression of transient receptor potential (TRP) ion channel of the vanilloid type 1 (TRPV1) and brain-derived neurotrophic factor (BDNF) were examined by immunohistochemistry and/or western blot. The inter-micturition intervals and the quantity of urine voided were obtained from analysis of cystometrograms. Results At 3 days post TNBS treatment, the protein level of TRPV1 was increased by 2-fold (p \u3c 0.05) in the inflamed distal colon when examined with western blot. TRPV1 was mainly expressed in the axonal terminals in submucosal area of the distal colon, and was co-localized with the neural marker PGP9.5. In sensory neurons in the dorsal root ganglia (DRG), BDNF expression was augmented by colonic inflammation examined in the L1 DRG, and was expressed in TRPV1 positive neurons. The elevated level of BDNF in L1 DRG by colonic inflammation was blunted by prolonged pre-treatment of the animals with the neurotoxin resiniferatoxin (RTX). Colonic inflammation did not alter either the morphology of the urinary bladder or the expression level of TRPV1 in this viscus. However, colonic inflammation decreased the inter-micturition intervals and decreased the quantities of urine voided. The increased bladder activity by colonic inflammation was attenuated by prolonged intraluminal treatment with RTX or treatment with intrathecal BDNF neutralizing antibody. Conclusion Acute colonic inflammation increases bladder activity without affecting bladder morphology. Primary afferent-mediated BDNF up-regulation in the sensory neurons regulates, at least in part, the bladder activity during colonic inflammation

Inhibition of Protein Aggregation: Supramolecular Assemblies of Arginine Hold the Key

BACKGROUND: Aggregation of unfolded proteins occurs mainly through the exposed hydrophobic surfaces. Any mechanism of inhibition of this aggregation should explain the prevention of these hydrophobic interactions. Though arginine is prevalently used as an aggregation suppressor, its mechanism of action is not clearly understood. We propose a mechanism based on the hydrophobic interactions of arginine. METHODOLOGY: We have analyzed arginine solution for its hydrotropic effect by pyrene solubility and the presence of hydrophobic environment by 1-anilino-8-naphthalene sulfonic acid fluorescence. Mass spectroscopic analyses show that arginine forms molecular clusters in the gas phase and the cluster composition is dependent on the solution conditions. Light scattering studies indicate that arginine exists as clusters in solution. In the presence of arginine, the reverse phase chromatographic elution profile of Alzheimer's amyloid beta 1-42 (Abeta(1-42)) peptide is modified. Changes in the hydrodynamic volume of Abeta(1-42) in the presence of arginine measured by size exclusion chromatography show that arginine binds to Abeta(1-42). Arginine increases the solubility of Abeta(1-42) peptide in aqueous medium. It decreases the aggregation of Abeta(1-42) as observed by atomic force microscopy. CONCLUSIONS: Based on our experimental results we propose that molecular clusters of arginine in aqueous solutions display a hydrophobic surface by the alignment of its three methylene groups. The hydrophobic surfaces present on the proteins interact with the hydrophobic surface presented by the arginine clusters. The masking of hydrophobic surface inhibits protein-protein aggregation. This mechanism is also responsible for the hydrotropic effect of arginine on various compounds. It is also explained why other amino acids fail to inhibit the protein aggregation

Health-related quality of life in patients with interstitial cystitis/bladder pain syndrome and frequently associated comorbidities

PURPOSE: To estimate the association of chronic non-urologic conditions [i.e., fibromyalgia (FM), chronic fatigue syndrome (CFS), and irritable bowel syndrome (IBS)] with health-related quality of life (HRQOL) in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: A total of 276 women with established diagnoses of IC/BPS completed a telephone interview which included demographics, self-reported medical conditions, the SF-36 health survey, and the interstitial cystitis symptom index (ICSI). Multivariate linear regression analysis was used to identify correlates of SF-36 physical and mental component summary scores. RESULTS: Mean patient age was 45.1 (SD 15.9) years, and 83 % of the subjects were white. Mean values for the SF-36 Physical Component Score (PCS) and Mental Component Score (MCS) means were 39 (SD 14) and 45 (SD 12), respectively, indicating significant HRQOL reductions. Mean ICSI score was 11.27 (SD = 4.86). FM and IBS were significantly associated with worse SF-36 scores: −8 points on the PCS (p <0.001) and −6 points on the MCS (p <0.001). CFS and the presence of other pelvic conditions (overactive bladder, vulvodynia, endometriosis) were not significantly associated with SF-36 PCS and MCS scores. CONCLUSIONS: In patients with IC/BPS, the presence of FM, CFS, and IBS has a significant association with HRQOL, equivalent in impact to the bladder symptoms themselves. These results emphasize the importance of a multidisciplinary approach to treating patients with IC/BPS and other conditions