Jiang Chunxiang, Caskurlu Aysegul, Ganesh Thota, Dingledine Ray
Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, 30322, Georgia.
Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
Brain Behav Immun Health. 2020 Aug 25;8:100132. doi: 10.1016/j.bbih.2020.100132. eCollection 2020 Oct.
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.
长期的认知和情感障碍是脓毒症幸存者的常见问题，这削弱了他们的职业能力和日常生活能力。据报道，神经炎症在包括癫痫、阿尔茨海默病（AD）和中风在内的不同疾病的认知缺陷发展中起关键作用。用脂多糖（LPS）（一种革兰氏阴性菌产生的内毒素）处理的小鼠表现出强烈但短暂的神经炎症，并出现长期记忆和情感问题。在本研究中，我们检验了这样一个假设：对前列腺素E2的EP2受体进行药理学阻断可减轻神经炎症，并预防LPS诱导的脓毒症相关性脑病（SAE）小鼠模型中的长期情感和记忆缺陷。我们的结果表明，EP2拮抗剂TG6-10-1可促进体重恢复，减轻由炎性细胞因子和小胶质细胞增生判断的神经炎症，防止突触蛋白丢失，并改善蔗糖偏好试验中的抑郁样行为以及新物体识别试验中的记忆丧失。我们的结果指出了一条改善脓毒症幸存者神经炎症以及长期情感和认知问题的新途径。
