Inhibition of the Prostaglandin EP2 Receptor Prevents Cognitive Impairment in a Model of Bacterial Sepsis
Abstract
Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection and can produce sepsis-associated encephalopathy (SAE), including acute delirium and longer-term cognitive impairment. Prostaglandin-E2 signaling through the EP2 receptor contributes to neuroinflammation and cognitive dysfunction in several experimental settings, but its role in post-sepsis cognitive impairment is unclear. Here, we characterize the inflammatory profile of hippocampus, kidney and blood after cecum ligation and puncture (CLP), which induces sepsis. An EP2 receptor antagonist was administered after CLP, and recognition memory was assessed seven days later by the novel object recognition test. Levels of the synaptic proteins, PSD-95 and synaptophysin, were also evaluated by western blot. CLP produced transient hypothermia, progressive weight loss, sickness behavior, splenomegaly, altered blood-cell counts, and persistent elevations in neutrophil-to-lymphocyte and monocyte-to-lymphocyte ratios. TNFα and CCL2 mRNA levels were persistently elevated in hippocampus and there was a larger and broader cytokine induction in kidney. Administration of EP2 antagonist TG6-10-1 at 2 and 26 h after CLP did not significantly alter survival, body weight, sickness behavior, or peripheral inflammatory measures. Nevertheless, TG6-10-1 prevented the CLP-associated deficit in novel object recognition and prevented the reduction in cortical PSD-95 abundance observed at day 7. These findings identify EP2 receptor signaling as a contributor to cognitive impairment after CLP and support further investigation of EP2 antagonism as a potential strategy for SAE-related cognitive dysfunction.
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BibTeX
@misc{jiang2026inhibition,
title = {{Inhibition of the Prostaglandin EP2 Receptor Prevents Cognitive Impairment in a Model of Bacterial Sepsis}},
author = {Chunxiang Jiang and Radhika Amaradhi and Thota Ganesh and Dingledine Ray},
howpublished = {Research Square},
year = {2026},
month = oct,
doi = {10.21203/rs.3.rs-11125792/v1},
url = {https://doi.org/10.21203/rs.3.rs-11125792/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Inhibition of the Prostaglandin EP2 Receptor Prevents Cognitive Impairment in a Model of Bacterial Sepsis
AU - Chunxiang Jiang
AU - Radhika Amaradhi
AU - Thota Ganesh
AU - Dingledine Ray
PY - 2026
DA - 2026/10/30
PB - Research Square
DO - 10.21203/rs.3.rs-11125792/v1
UR - https://doi.org/10.21203/rs.3.rs-11125792/v1
AB - Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection and can produce sepsis-associated encephalopathy (SAE), including acute delirium and longer-term cognitive impairment. Prostaglandin-E2 signaling through the EP2 receptor contributes to neuroinflammation and cognitive dysfunction in several experimental settings, but its role in post-sepsis cognitive impairment is unclear. Here, we characterize the inflammatory profile of hippocampus, kidney and blood after cecum ligation and puncture (CLP), which induces sepsis. An EP2 receptor antagonist was administered after CLP, and recognition memory was assessed seven days later by the novel object recognition test. Levels of the synaptic proteins, PSD-95 and synaptophysin, were also evaluated by western blot. CLP produced transient hypothermia, progressive weight loss, sickness behavior, splenomegaly, altered blood-cell counts, and persistent elevations in neutrophil-to-lymphocyte and monocyte-to-lymphocyte ratios. TNFα and CCL2 mRNA levels were persistently elevated in hippocampus and there was a larger and broader cytokine induction in kidney. Administration of EP2 antagonist TG6-10-1 at 2 and 26 h after CLP did not significantly alter survival, body weight, sickness behavior, or peripheral inflammatory measures. Nevertheless, TG6-10-1 prevented the CLP-associated deficit in novel object recognition and prevented the reduction in cortical PSD-95 abundance observed at day 7. These findings identify EP2 receptor signaling as a contributor to cognitive impairment after CLP and support further investigation of EP2 antagonism as a potential strategy for SAE-related cognitive dysfunction.
SN - 2693-5015
ER -