Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mic
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Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mice Rong Gao,1 Yuan-hui Tang,2 Jian-hua Tong,2 Jian-Jun Yang,2 Mu-huo Ji,1,2,3 and Si-hai Zhu1,2,3
Abstract—Sepsis-associated encephalopathy (SAE) is a frequent complication in critically ill patients and is associated with long-term cognitive impairments. However, the pathophysiology underlying SAE is poorly understood and the pharmacologic treatment is lacking. The purpose of the present study was to investigate the effects of erythropoietin (EPO) on cognitive impairments in an animal model of SAE induced by peripheral administration of lipopolysaccharide (LPS). Mice were randomly divided into the sham+ vehicle, sham +EPO, LPS+ vehicle, and LPS+ EPO groups. EPO was administrated 30 min after the LPS administration and daily afterward for 2 days. Behavioral tests were performed on days 6 and 7 with open field and fear conditioning tests, respectively. The survival rate was estimated by the Kaplan– Meier method. The levels of proinflammatory responses, oxidative stress, and apoptosis-related markers were measured in the hippocampus at the indicated time points. The synaptic morphometry changes in the CA1 region were observed with transmission electron microscopy. Our results showed that LPS administration resulted in high mortality rate and cognitive impairments, which were accompanied by increased expressions of interleukin-1β, malondialdehyde, cleaved caspase-3, and abnormal synaptic morphometry changes in the hippocampus. Notably, EPO treatment reversed the cognitive impairments and rescued the brain pathology induced by LPS administration. In conclusion, our data suggested that treatment with EPO reduced the mortality rate and ameliorated cognitive impairments in an animal model of SAE. KEY WORDS: sepsis; cognitive impairments; hippocampus; erythropoietin.
INTRODUCTION Sepsis-associated encephalopathy (SAE) remains a frequent complication in critically ill patients and is an independent risk factor for the poorer prognosis [1–3]. Clinical studies demonstrate that the brain may be one of the first organs affected during sepsis [4], and septic patients often suffer from cognitive impairments and
1
Department of Emergency and Intensive Care Medicine, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nanjing University of Chinese Medicine, Nanjing 210014, China 2 Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China 3 To whom correspondence should be addressed at Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China. E-mails: [email protected]; [email protected]
functional disability after discharge from the hospital [1]. Animal models have also shown the long-term alternations in the behavior, learning, and memory after sepsis development. However, the mechanisms underlying SAE remain to be determined and no specific pharmacological therapy is currently availa
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