MP28-04 CHRONIC BLADDER OUTLET OBSTRUCTION CAUSES NLRP3-DEPENDENT INFLAMMATION IN THE HIPPOCAMPUS AND DEPRESSION IN RATS

Abstract

INTRODUCTION AND OBJECTIVE: Numerous reports, the Epidemiology of LUTS (EpiLUTS) study, support an association between urinary dysfunction and mood disorders such as depression and anxiety. Regarding benign prostatic hyperplasia, patients with a concurrent diagnosis of clinical depression have a higher rate of reported LUTS while patients with significant BPH symptoms are more likely to develop depression. This suggests a bidirectional relationship between urinary dysfunction and mood disorders, but a causative mechanism has never been postulated. A previous study from our laboratory demonstrated that chemical cystitis elicits NLRP3-dependent inflammation in the hippocampus in rats and was associated with depressive behavior. Since BOO evokes a local inflammatory response in the bladder, we hypothesize that it will also induce inflammation in the hippocampus and depressive behavior. Here, we investigate this hypothesis and define an immunologically driven bladder-brain axis. METHODS: Female rats were divided into 4 groups: control, sham, BOO or BOO + gly (glyburide; an NLRP3 inhibitor). BOO was created by urethral ligation over a 1 mm transurethral catheter. Glyburide was provided by subcutaneous pellet (50 mg, 21 day release). Rats were analyzed 12 weeks post-op. Hippocampal inflammation was quantitated by Evan’s blue extravasation, microglia and neurogenesis by IbA-1 and Ki-67 staining, respectively. Depression was assessed by open field and sucrose preference tests. RESULTS: There was an increase in inflammation (Evans blue) in the hippocampus in BOO rats which was blocked by glyburide. This was accompanied by an increase in activated microglia and a decrease in neurogenesis. In addition, there was a decrease in exploratory behavior in the open field behavioral assay and a decrease in sucrose preference in the BOO rats, both of which are signs of depression. Like inflammation, these symptoms were diminished to control values by glyburide. CONCLUSIONS: BOO, a bladder-localized event, stimulates NLRP3-dependent inflammation in the hippocampus of rat after 12 weeks and this inflammation causes depression. This is the first-ever causative explanation of the previously anecdotal link between BOO and depression.Source of Funding: NIDDK: R01DK103534 (PI - Purves)