Inhibition of the prostaglandin EP2 receptor prevents long-term cognitive impairment in a model of systemic inflammation

• Type of Material: Article
• Authors: Chunxiang Jiang, Emory University; Aysegul Caskurlu, Emory University; Thota Ganesh, Emory University; Ray Dingledine, Emory University
• Language: English
• Date: 2020-10-01
• Publisher: Elsevier Inc
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Author(s)
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbih.2020.100132
• Title of Journal or Parent Work: Brain, Behavior, and Immunity - Health
• Volume: 8
• Start Page: 100132
• End Page: 100132
• Grant/Funding Information: This work was supported by the National Institutes of Health, Grant Number R01 NS097776 (RD), U01 AG052460 (TG), and R01 NS112308 (RD).
• Keywords: Sepsis-associated encephalopathy; Novel object recognition test; Sucrose preference test; Neuroinflammation; EP2 receptor; Lipopolysaccharide
• Research Categories: Health Sciences, Pharmacology

Abstract

Long-term cognitive and affective impairments are common problems in the survivors of sepsis, which weakens their vocational and daily life ability. Neuroinflammation has been reported to exert a key role in the development of cognitive deficit in different disorders including epilepsy, Alzheimer's disease (AD) and stroke. Mice treated with lipopolysaccharide (LPS), an endotoxin produced by gram-negative bacteria, show a robust but short-lived neuroinflammation and develop long-term memory and affective problems. In this study, we test the hypothesis that pharmacological blockade of the EP2 receptor for prostaglandin E2 reduces neuroinflammation and prevents long-term affective and memory deficits in a mouse model of LPS-induced, sepsis-associated encephalopathy (SAE). Our results show that an EP2 antagonist, TG6-10-1, promotes the recovery of body weight, mitigates neuroinflammation as judged by inflammatory cytokines and microgliosis, prevents the loss of synaptic proteins, and ameliorates depression-like behavior in the sucrose preference test as well as memory loss in the novel object recognition test. Our results point to a new avenue to ameliorate neuroinflammation and long-term affective and cognition problems of sepsis survivors.