The present study investigated whether infusion of brain-derived neurotrophic factor (BDNF) could ameliorate stress-induced impairments in spatial learning and memory as well as hippocampal long-term potentiation (LTP) of rats. Chronic immobilization stress (2 h/day x 7 days) significantly impaired spatial performance in the Morris water maze, elevated plasma corticosterone, and attenuated LTP in hippocampal slices from these animals as compared with normal control subjects. BDNF was infused into the left hippocampus (0.5 mul/h) for 14 days, beginning 7 days before the stress exposure. The BDNF group was protected from the deleterious effects of stress and performed at a level indistinguishable from normal control animals despite the presence of elevated corticosterone. BDNF alone and sham infusions had no effect on performance or LTP. These results demonstrate that spatial learning and memory, and LTP, a candidate neural substrate of learning and memory, are compromised during chronic stress, and may be protected by BDNF administration.
Aims Two phase 2 studies were conducted to assess the efficacy and safety of lidocaine‐releasing intravesical system (LiRIS) in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) with (Study 001; NCT02395042) or without, (Study 002; NCT02411110) Hunner lesions (HL). Methods Both were multicenter, randomized, double‐blind, placebo‐controlled, and enrolled women aged ≥18 years. In Study 001, patients were randomized 2:1:1 to LiRIS 400 mg/LiRIS 400 mg, placebo/LiRIS 400 mg, or placebo/placebo for a continuous 28 (2 × 14)‐day period. In Study 002, patients were randomized 1:1 to LiRIS 400 mg or placebo for a continuous (single treatment) 14‐day period. Results In total, 59 and 131 patients received treatment in Studies 001 and 002, respectively. There was no statistically significant difference in the primary endpoint, the change from baseline to Week 4 of follow‐up post‐removal in mean daily average bladder numeric rating scale (NRS) pain score in either study (Study 001: placebo/placebo, −1.6; LiRIS/LiRIS, −2.7, p = 0.142; placebo/LiRIS, −2.5, p = 0.319; Study 002: LiRIS −1.2; placebo, −1.5, p = 0.505). There was no statistically significant difference between groups in daily worst NRS pain score, number of micturitions/day or urgency episodes/day. There was no clear trend for reduction in number of HL for LiRIS vs placebo. The frequency of treatment‐emergent adverse events was similar between treatment groups in both studies; most were mild or moderate intensity. Conclusion These studies did not demonstrate a treatment effect of LiRIS 400 mg compared with placebo, either in patients with IC/BPS with HL, or in those without HL.
Interstitial cystitis (IC) is a heterogeneous condition with urinary and systemic symptoms. Clinically relevant phenotyping has been a challenge, but some patients, especially those with Hunner's Ulcers, have evidence for immune activation. We hypothesize that gene expression signatures can be used as a biomarker to phenotype patients with IC and predict response to specific therapies.METHODS: As part of a clinical trial of oral cyclosporine A (CyA), blood was collected from 26 IC patients prior to treatment and after 3 months of CyA at 3 mg/kg/d as well as from 20 asymptomatic controls. A training set of 6 controls and 6 IC patients including those who did or did not respond to CyA was initially run. RNA was isolated from whole blood (Tempus tubes) and analyzed using Illumina HT-12 v4 BeadChip arrays. PANTHER pathway analysis and DAVID functional classification were used for annotation and grouping of differently expressed genes.RESULTS: Using the criteria of fold-changes less than 0.5 or greater than 2 and p<.05, we found 155 unique genes that were differently expressed in the blood of IC patients vs controls representing 55 pathways including inflammation mediated by chemokines and cytokines, T cell activation, integrin signaling, angiogenesis, and apoptosis. Comparing patients who subsequently had significant clinical improvement with CyA therapy to those who didn't improve, there were 37 genes with at least two fold differential expression. Using DAVID functional annotation clustering, these genes represented responses in inflammation, wound healing, and innate immunity. Finally, following CyA therapy, interleukin signaling changed in all patients but other pathways that changed were distinct between responders and non-responders. In CyA responders, the altered gene expression pathways were related to matrix remodeling (plasminogen activating cascade) and pain modulation (cannabinoid and dopamine receptor signaling).CONCLUSIONS: Gene expression signatures in whole blood distinguished between IC patients and controls as well as between patients who would subsequently improve with CyA therapy. Pathways altered following CyA therapy in the responders could serve as potential targets for new drug development.
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