A possible mechanism underlying mood disorders associated with LUTS: Chronic bladder outlet obstruction causes NLRP3-dependent inflammation in the hippocampus and depressive behavior in rats
Open accessAbstract
AIMS: Reports link urinary dysfunction and mood disorders, such as depression, but a causative mechanism has never been postulated. Contemporary discoveries demonstrate a local inflammatory response in peripheral organs can trigger inflammation in the brain, particularly the hippocampus, mediated through the NLRP3 inflammasome. Critically, central inflammation causes depressive behavior. Since bladder outlet obstruction (BOO) evokes a local inflammatory response in the bladder, we hypothesize it will induce NLRP3-dependent inflammation in the hippocampus and depressive behavior. METHODS: There were four groups of rats: control, sham, BOO, or BOO + glyburide (an NLRP3 inhibitor). BOO was created by urethral ligation over a 1 mm catheter. Sham was tied loosely. Glyburide was provided by slow-release pellet (subcutaneous 50 mg, 21 day, replaced as needed). Rats were analyzed 12 weeks post-op for: hippocampal inflammation, microglial density, neurogenesis, and depression symptoms (open field and sucrose preference). RESULTS: BOO elicited hippocampal inflammation, accompanied by an increase in activated microglia (22%) and a decrease in neurogenesis (35%), which was blocked by glyburide. In addition, BOO rats displayed anxiety (57% decrease in exploratory behavior in the open field assay) and anhedonia (21% decrease in sucrose preference), two symptoms of depression. Like inflammation, these symptoms were diminished by glyburide to levels not statistically significantly different from controls. CONCLUSIONS: BOO, a bladder-localized event, stimulates NLRP3-dependent inflammation in the rat hippocampus after 12 weeks and this inflammation causes depressive behavior. This is the first mechanistic explanation of the link between BOO and depression and provides evidence for a distinct bladder-brain axis.
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Bladder outlet obstruction has been linked to inflammation and depressive behaviour in rodent research.
“For example, bladder outlet obstruction has been linked to inflammation and depressive behaviour in rodent research [24].”
From Biological, Psychological, and Social Determinants of Depression: A Review of Recent Literature (2021) · cites this paper as [24]
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- Authors
- Hughes, F. M., Hirshman, N. A., Malick, H. A., White, S. W., Jin, H., Harper, S. N., & Purves, J. T.
- Affiliations
- Duke Medical Center (US)
- Corresponding author
- Hughes, Francis M.
- ORCID
- Venue
- Neurourology and Urodynamics
- Publisher
- Wiley
- Published
- 2020-06-29
- Volume
- 39
- Issue
- 6
- Pages
- 1700-1707
- ISSN
- 0733-2467 (ISSN-L)
- 1520-6777
- PMC
- PMC8793365
- OpenAlex
- W3038475976
- Cited by
- 11
- References
- 26
- Citations by year
- 2026: 3 · 2025: 1 · 2023: 3 · 2022: 2 · 2021: 2
- FWCI
- 0.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurourology and Urodynamics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK103534, DK117890)
- School of Medicine, Duke University (Poindexter Fellowship, intramural funds)
- Urology Care Foundation
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Urology › Urinary Bladder and Prostate Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- lower urinary tract symptoms, bladder outlet obstruction, depression, NLRP3 inflammasome, hippocampal inflammation, microglial activation, neurogenesis, glibenclamide, anxiety, anhedonia, neuroinflammation
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Urinary Bladder Neck Obstruction, Depression, Disease Models, Animal, Female, Hippocampus, Inflammation, Rats, Sprague-Dawley, Microglia, Rats, Inflammasomes, Lower Urinary Tract Symptoms
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