{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T11:39:00Z","timestamp":1774352340925,"version":"3.50.1"},"reference-count":55,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,12,28]],"date-time":"2017-12-28T00:00:00Z","timestamp":1514419200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Septic encephalopathy with confusion and agitation occurs early during sepsis and contributes to the severity of the disease. A decrease in the sphingosine\u20101\u2010phosphate (S1P) blood levels has been shown in patients and in animal models of sepsis. The lipid mediator S1P is known to be involved in endothelial barrier function in a context\u2010dependent manner. We utilized lipopolysaccharide (<jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content>)\u2010injected mice as a model for septic encephalopathy and first performed tracer permeability assays to assess the blood\u2013brain barrier (<jats:styled-content style=\"fixed-case\">BBB<\/jats:styled-content>) breakdown in\u00a0vivo. At time points corresponding to the <jats:styled-content style=\"fixed-case\">BBB<\/jats:styled-content> breakdown post <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> injection, we aimed to characterize the regulation of the sphingolipid signaling pathway at the <jats:styled-content style=\"fixed-case\">BBB<\/jats:styled-content> during sepsis. We measured sphingolipid concentrations in blood, in mouse brain microvessels (<jats:styled-content style=\"fixed-case\">MBMV<\/jats:styled-content>s), and brain tissue. We also analyzed the expression of S1P receptors, transporters, and metabolizing enzymes in <jats:styled-content style=\"fixed-case\">MBMV<\/jats:styled-content>s and brain tissue. Primary mouse brain microvascular endothelial cells (<jats:styled-content style=\"fixed-case\">MBMEC<\/jats:styled-content>s) were isolated to evaluate the effects of <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> on transendothelial electrical resistance (<jats:styled-content style=\"fixed-case\">TEER<\/jats:styled-content>) as a measure of permeability <jats:italic>in\u00a0vitro<\/jats:italic>. We observed a relevant decrease in S1P levels after <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> injection in all three compartments (blood, <jats:styled-content style=\"fixed-case\">MBMV<\/jats:styled-content>s, brain tissue) that was accompanied by an increased expression of the S1P receptor type 1 and of sphingosine kinase 1 on one hand and of the S1P degrading enzymes lipid phosphate phosphatase 1 (<jats:styled-content style=\"fixed-case\">LPP<\/jats:styled-content>1) and S1P phosphatase 1 on the other hand, as well as a down\u2010regulation of sphingosine kinase 2. Application of <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> to a monolayer of primary <jats:styled-content style=\"fixed-case\">MBMEC<\/jats:styled-content>s did not alter <jats:styled-content style=\"fixed-case\">TEER<\/jats:styled-content>, but serum from <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content>\u2010treated mice lead to a breakdown of the barrier compared to serum from vehicle\u2010treated mice. We observed profound alterations of the sphingolipid metabolism at the <jats:styled-content style=\"fixed-case\">BBB<\/jats:styled-content> after <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> injection that point toward a therapeutic potential of drugs interfering with this pathway as novel approach for the detrimental overwhelming immune response in sepsis.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14236-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p><jats:bold>Read the Editorial Highlight for this article on page<\/jats:bold> <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.1111\/jnc.14246\">115<\/jats:ext-link>.<\/jats:p><jats:p><jats:bold>Cover Image<\/jats:bold> for this Issue: doi. <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1111\/jnc.14161\">10.1111\/jnc.14161<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14236","type":"journal-article","created":{"date-parts":[[2017,10,11]],"date-time":"2017-10-11T07:42:49Z","timestamp":1507707769000},"page":"172-185","source":"Crossref","is-referenced-by-count":54,"title":["Alteration of sphingolipid metabolism as a putative mechanism underlying <scp>LPS<\/scp>\u2010induced <scp>BBB<\/scp> disruption"],"prefix":"10.1111","volume":"144","author":[{"given":"Rajkumar","family":"Vutukuri","sequence":"first","affiliation":[{"name":"Pharmazentrum Frankfurt Institute for General Pharmacology and Toxicology Goethe University Frankfurt 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