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

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.