Assess the effects of bazedoxifene acetate (BZA) on delirium-like phenotypes in a urinary tract infection (UTI) model of delirium.

Delirium occurs in tens of millions of patients with UTI every year and is associated with increased mortality, prolonged hospitalization, and a three-fold increased risk of dementia. In prior preclinical and clinical studies, we demonstrated that the interleukin-6 (IL-6) trans-signaling pathway (TSP) may underlie the pathogenesis of UTI-induced delirium. We also demonstrated an ameliorative role for 17β-estradiol in mitigating these phenotypes via pleiotropic mechanisms including attenuation of IL-6 TSP. Accordingly, we hypothesized that BZA, an IL-6 TSP inhibitor and selective estrogen receptor modulator, would ameliorate structural and functional delirium-like phenotypes in a UTI model of delirium.

UTI was induced in wild-type mice and treated with either BZA or vehicle. Cleaved caspase-3 (CC3), an early apoptotic/candidate neuronal marker of delirium-like behavior, was evaluated using immunohistochemistry. Delirium-like behaviors were assessed using Open Field, Elevated Plus Maze, Y-maze, and Novel Object assays.

Compared to vehicle-treated mice (n=10), BZA-treated (n=10), UTI mice had significantly lower levels of CC3 in the frontal cortex (p = 0.04) and hippocampus (p = 0.0007). These structural changes were accompanied by improved delirium-like behaviors in BZA- compared to vehicle-treated mice, including increased spontaneous alternations in Y-Maze (p=.0263) and more time spent oriented toward the novel object (p=0.0315). Significantly fewer fecal pellets were collected from BZA- compared to vehicle-treated mice (p=0.0001). There was a significant inverse correlation between cortical CC3 and performance on Y-maze (R2 = 0.27, p = 0.015) and a significant positive correlation between hippocampal CC3 and the number of fecal pellets (R2 = 0.55, p = 0.002).

These data indicate a neuroprotective role for BZA in ameliorating structural and functional delirium-like phenotypes after UTI and provide preclinical justification for clinical trials using BZA to ameliorate delirium.