Presentation Authors: Todd Purves*, Nathan Hirshman, Huixia Jin, Isabelle Doan, Simon White, Shelby Harper, Francis Hughes Jr., Durham, NC
Introduction: Interstitial Cystitis (IC) is often associated with psychological co-morbidities, in particular depression. Breakthroughs in other fields have shown that peripheral disease can result in inflammation in the brain which is responsible for various mood disorders. Moreover, the NLRP3 inflammasome, which is present in microglia and functions to mature proinflammatory cytokines, appears critical in triggering neuroinflammation. Thus, we sought to explore if NLRP3-induced neuroinflammation is present in a rodent model of IC and if it produces depressive behavior. We have employed the imperfect but best studied model of IC, the cyclophosphamide (CP)-treated rat. Importantly, CP and its metabolites do not cross the blood brain barrier, so that any neuroinflammation is secondary to the peripheral insult.
Methods: Rats were injected (150 mg/kg, i.p.) with CP while medications (NLRP3 inhibitor glyburide, 2.5 mg/kg, p.o.; antidepressant fluoxetine, 1 mg/ml, i.p.) were administered pre-operatively and throughout the experiment. After 24 h, brains were harvested and caspase-1 activity (cleavage of YVAD-afc), inflammation (Evanâ€™s blue) and histology (H&E) were measured. Depression assays began 24 h after CP injection and finished 24 h later. For forced swim, rats were placed in an inescapable water cylinder for 5 min and the time spent immobile recorded (10 min training period 24 h earlier). For sucrose preference the consumption of plain vs. sucrose-laden water was monitored over 24 h.
Results: CP triggered a significant increase in caspase-1 activity and inflammation in the hippocampus but not in the pons, that was blocked with the NLRP3 inhibitor. Histology indicated breakdown of the blood brain barrier with activated microglia in the dentate gyrus, again dependent on NLRP3 activation. Finally, CP-treated rats displayed depression symptoms in 2 behavioral assays that was prevented by both the NLRP3 inhibitor and an antidepressant (Figure 1).
Conclusions: The results demonstrate NLRP3-induced hippocampal inflammation, resulting from CP-induced cystitis, is responsible for depression in these rats. This study provides the first-ever causative explanation of the previously anecdotal link between IC and depression.
Source of Funding: Research reported in this publication was supported by the National Institute Of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under Award Number R01DK103534.