Discovery of novel protective agents for infection-related delirium through bispectral electroencephalography

Abstract

Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.

Fig. 1

Experimental schedules showing the timing of testing putative efficacy of haloperidol, P7C3-A20, and minocycline in the mouse LPS model of infection-related delirium.

Fig. 2. Haloperidol.

A sBSEEG scores as a function of haloperidol treatment in young and aged mice. The sBSEEG scores were plotted on the y-axis, and recording times were displayed on the x-axis. Daytime/night was shown as yellow/gray lines on the background of the x-axis. B AUC of experiments comparing the vehicle and haloperidol group in young and aged mice. The AUC (% vehicle) was plotted on the y-axis to compare the vehicle with the haloperidol group.

Fig. 3. P7C3-A20.

A sBSEEG scores as a function of P7C3-A20 treatment in young and aged mice. The sBSEEG scores were plotted on the y-axis, and recording times were displayed on the x-axis. Daytime/night was shown as yellow/gray lines on the background of the x-axis. B AUC of experiments comparing the vehicle and P7C3-A20 group in young and aged mice. The AUC (% vehicle) was plotted on the y-axis to compare the vehicle with the P7C3-A20 group.

Fig. 4. Minocycline.

A sBSEEG scores as a function of minocycline treatment in young and aged mice. The sBSEEG scores were plotted on the y-axis, and recording times were displayed on the x-axis. Daytime/night is shown as yellow/gray lines on the background of the x-axis. B AUC of experiments comparing the vehicle and minocycline group in young and aged mice. The AUC (% Vehicle) was plotted on the y-axis to compare the vehicle with the minocycline group.