Summary: Treatment with estrogen significantly lowered inflammatory markers and reduced delirium-like behaviors in mouse models of urinary tract infection.
Source: Cedars-Sinai Medical Center
Delirium frequently occurs in women who develop urinary tract infections (UTIs), particularly after menopause. Researchers at Cedars-Sinai used laboratory mice to examine whether estrogen—commonly prescribed in hormone replacement therapy—can prevent delirium-like symptoms. Their findings, published in the peer-reviewed journal Scientific Reports, suggest estrogen reduces both inflammation and behavioral signs resembling delirium.
“There has been a resurgence of interest in hormone replacement therapy, and this study, which builds on our previous work, shows that it may be a tool to mitigate delirium,” said Shouri Lahiri, MD, director of the Neurosciences Critical Care Unit and Neurocritical Care Research at Cedars-Sinai and senior author of the study. “I think it is a major step toward a clinical trial of estrogen in human patients with UTIs.”
Delirium is characterized by sudden changes in attention, awareness and cognition. Lahiri noted that it is a common and sometimes overlooked problem in older women with UTIs. Clinically, when an older woman presents confused in the hospital, one of the immediate checks is whether a urinary tract infection might be present.
Past work from this group identified interleukin-6 (IL-6), an immune-signaling protein, as a key mediator linking peripheral infection to brain dysfunction. Events such as lung injury or UTI can elevate IL-6, which then circulates to the brain and contributes to disorientation and confusion. Because estrogen is known to suppress IL-6, the researchers designed experiments to test whether 17β-estradiol could prevent UTI-induced delirium-like effects.
In the study, investigators compared behaviors and biological markers in pre- and postmenopausal mouse models after inducing UTIs. Mice that had undergone ovariectomy to model menopause displayed anxiety and confusion in specialized behavioral tests—signs consistent with delirium-like phenotypes—whereas non-oophorectomized controls did not show those changes.
Administration of 17β-estradiol to oophorectomized mice markedly reduced plasma IL-6 levels and improved performance in behavioral assays. Importantly, the differences in behavior were not explained by greater bacterial burden: urine bacterial counts were similar between groups, indicating the protective effect was not due to reduced infection itself but likely to modulation of the immune response and direct neuronal protection.
To examine direct neuronal effects, the team performed in vitro experiments they describe as a “UTI in a dish.” Individual neurons were exposed to an IL-6–rich inflammatory cocktail to mimic infection-related injury. Adding estrogen to that cocktail reduced neuronal injury, indicating 17β-estradiol may act through at least two mechanisms: lowering systemic IL-6 and providing direct neuroprotection.
Open questions remain about the precise molecular pathways by which estrogen protects neurons and which patient groups would derive the most benefit. Before moving to human trials, researchers must determine which patients with UTIs are most likely to develop delirium and the optimal timing and dosing for estrogen treatment.
“Currently, it is common practice to treat UTI-induced delirium using antibiotics, even though there are no clinical trials that indicate this practice is effective and it is not supported by clinical practice guidelines,” said Nancy Sicotte, MD, chair of the Department of Neurology and the Women’s Guild Distinguished Chair in Neurology at Cedars-Sinai. “This work is an important step in determining whether modulating immune response via estrogen replacement or other means is a more effective treatment.”
The team is also investigating sex differences in delirium vulnerability and response to treatment—an important area not covered in this particular study. Effective interventions for delirium are clinically significant because delirium is a known risk factor for longer-term cognitive decline, including Alzheimer’s disease and related dementias.
About this neurology research news
Author: Press Office
Source: Cedars-Sinai Medical Center
Contact: Press Office – Cedars-Sinai Medical Center
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Original Research: Open access. “17β-estradiol ameliorates delirium-like phenotypes in a murine model of urinary tract infection” by Gena Guidry et al., Scientific Reports
Abstract
17β-estradiol ameliorates delirium-like phenotypes in a murine model of urinary tract infection
Urinary tract infections commonly precipitate delirium-like states, and advanced age coinciding with the postmenopausal period increases risk. Earlier work demonstrated a pathological role for interleukin-6 (IL-6) in mediating delirium-like phenotypes in a mouse UTI model. Estrogen has been implicated in lowering peripheral IL-6 expression, but it was not known whether reduced circulating estrogen contributes to heightened delirium susceptibility after menopause.
In this study, female C57BL/6J mice underwent ovariectomy to model the postmenopausal state, received transurethral inoculation with Escherichia coli to induce UTI, and were treated with 17β-estradiol. Delirium-like behaviors were assessed before and after UTI induction and estrogen treatment. Compared to controls, mice treated with 17β-estradiol exhibited less neuronal injury, improved behavioral outcomes, and reduced IL-6 in plasma and frontal cortex. In vitro experiments further indicated that 17β-estradiol may offer direct neuronal protection, suggesting multiple protective mechanisms. These results support a beneficial role for 17β-estradiol in reducing acute UTI-induced structural and functional delirium-like phenotypes and provide preclinical justification for exploring 17β-estradiol as a therapeutic strategy to mitigate delirium following UTI.