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Sepsis-induced selective loss of NMDA receptors modulates hippocampal neuropathology in surviving septic mice.

ABSTRACT: Sepsis-induced neuroinflammation plays an important role in sepsis-related brain dysfunction. However, the molecules that are targeted during neuroinflammation resulting from sepsis-induced brain dysfunction remain unclear. Herein, we tried to investigate the expression and roles of NMDA receptor subunits during sepsis-related brain dysfunction.Sepsis was induced by cecal ligation and perforation (CLP) or by a single intraperitoneal injection of lipopolysaccharide (LPS, 8 mg/kg) in C57BL/6J mice. The NMDA receptor co-agonist D-serine was injected intraperitoneally for 3 days (500 mg/kg/day) to compensate for the loss of NMDA receptors. The behaviors of mice were tested in the Barnes maze and in the open field test. The mice were euthanized at the indicated time points. The brains were collected to detect the following: the levels of synaptophysin and NMDA receptor subunits GluN2A, GluN2B and GluN1 (by Western blot and RT-PCR); the number of CA1 neurons (by Nissl staining); neuronal activity (by p-CREB staining); neuroinflammation (by staining of Iba-1 and inflammatory factors IL-1?, TNF-?, NLRP3); and the levels of oxidative stress [by dihydroethidium (DHE)].Sepsis selectively decreased the protein and mRNA levels of GluN2A, GluN2B and GluN1 but not the levels of synaptophysin or the neuronal number in the hippocampus of mice in either of the classic CLP-induced or LPS-induced sepsis models during the first 7 days after sepsis. Intraperitoneal injection of D-serine obviously limited the lipopolysaccharide-induced changes, including the impairment of learning and memory, the loss of NMDA receptor subunits, robust neuroinflammation, the levels of ROS stress and the decrease of p-CREB in the hippocampus of mice.These data suggest that the sepsis-induced selective loss of NMDA receptors modulates hippocampal neuropathology in the mice that survived sepsis, and the data show that NMDA receptors are potential targets for the improvement of brain dysfunction in sepsis survivors.

SUBMITTER: Zhang S

PROVIDER: S-EPMC5703474 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Sepsis-induced selective loss of NMDA receptors modulates hippocampal neuropathology in surviving septic mice.

Zhang Shuibing S Wang Xueqin X Ai Sha S Ouyang Wen W Le Yuan Y Tong Jianbin J

PloS one 20171127 11

<h4>Background</h4>Sepsis-induced neuroinflammation plays an important role in sepsis-related brain dysfunction. However, the molecules that are targeted during neuroinflammation resulting from sepsis-induced brain dysfunction remain unclear. Herein, we tried to investigate the expression and roles of NMDA receptor subunits during sepsis-related brain dysfunction.<h4>Methods</h4>Sepsis was induced by cecal ligation and perforation (CLP) or by a single intraperitoneal injection of lipopolysacchar ...[more]

PMID: 29176858

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Project description:ObjectiveTo identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock.DesignA consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations.MethodsEach committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science.ResultsThe Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction?ConclusionsWhile the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock.

Project description:ObjectivesTo develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction.DesignA panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process.MethodsThe panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate.ResultsThe panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 49 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 52 research priorities were identified.ConclusionsA large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.

Dataset Information

Sepsis-induced selective loss of NMDA receptors modulates hippocampal neuropathology in surviving septic mice.

Publications

Sepsis-induced selective loss of NMDA receptors modulates hippocampal neuropathology in surviving septic mice.

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