17β-estradiol ameliorates delirium-like phenotypes in a murine model of urinary tract infection

Urinary tract infections (UTIs) are common and frequently precipitate delirium-like states. Advanced age coincident with the postmenopausal period is a risk factor for delirium following UTIs. We previously demonstrated a pathological role for interleukin-6 (IL-6) in mediating delirium-like phenotypes in a murine model of UTI. Estrogen has been implicated in reducing peripheral IL-6 expression, but it is unknown whether the increased susceptibility of postmenopausal females to developing delirium concomitant with UTIs reflects diminished effects of circulating estrogen. Here, we tested this hypothesis in a mouse model of UTI. Female C57BL/6J mice were oophorectomized, UTIs induced by transurethral inoculation of E. coli, and treated with 17 beta-estradiol. Delirium-like behaviors were evaluated prior to and following UTI and 17 beta-estradiol treatment. Compared to controls, mice treated with 17 beta-estradiol had less neuronal injury, improved delirium-like behaviors, and less plasma and frontal cortex IL-6. In vitro studies further showed that 17 beta-estradiol may also directly mediate neuronal protection, suggesting pleiotropic mechanisms of 17 beta-estradiol-mediated neuroprotection. In summary, we demonstrate a beneficial role for 17 beta-estradiol in ameliorating acute UTI-induced structural and functional delirium-like phenotypes. These findings provide pre-clinical justification for 17 beta-estradiol as a therapeutic target to ameliorate delirium following UTI.

Automated summary

Urinary tract infections (UTIs) can lead to delirium-like states, and postmenopausal females are more susceptible to delirium following UTIs. It has been found that 17 beta-estradiol can reduce neuronal injury and improve delirium-like behaviors caused by UTIs, possibly by suppressing the expression of interleukin-6 (IL-6).