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Elevated blood and brain ammonia levels have been implicated in its pathogenesis, and astrocytes are the principal neural cells involved in this disorder. Since defective synthesis and release of astrocytic factors have been shown to impair synaptic integrity in other neurological conditions, we examined whether thrombospondin\u20101 (\n                    <jats:styled-content style=\"fixed-case\">TSP<\/jats:styled-content>\n                    \u20101), an astrocytic factor involved in the maintenance of synaptic integrity, is also altered in\n                    <jats:styled-content style=\"fixed-case\">CHE<\/jats:styled-content>\n                    . Cultured astrocytes were exposed to ammonia (\n                    <jats:styled-content style=\"fixed-case\">\n                      NH\n                      <jats:sub>4<\/jats:sub>\n                      Cl\n                    <\/jats:styled-content>\n                    , 0.5\u20132.5\u00a0mM) for 1\u201310\u00a0days, and\n                    <jats:styled-content style=\"fixed-case\">TSP<\/jats:styled-content>\n                    \u20101 content was measured in cell extracts and culture media. Astrocytes exposed to ammonia exhibited a reduction in intra\u2010 and extracellular\n                    <jats:styled-content style=\"fixed-case\">TSP<\/jats:styled-content>\n                    \u20101 levels. Exposure of cultured neurons to conditioned media from ammonia\u2010treated astrocytes showed a decrease in synaptophysin,\n                    <jats:styled-content style=\"fixed-case\">PSD95<\/jats:styled-content>\n                    , and synaptotagmin levels. Conditioned media from\n                    <jats:styled-content style=\"fixed-case\">TSP<\/jats:styled-content>\n                    \u20101 over\u2010expressing astrocytes that were treated with ammonia, when added to cultured neurons, reversed the decline in synaptic proteins. Recombinant\n                    <jats:styled-content style=\"fixed-case\">TSP<\/jats:styled-content>\n                    \u20101 similarly reversed the decrease in synaptic proteins. Metformin, an agent known to increase\n                    <jats:styled-content style=\"fixed-case\">TSP<\/jats:styled-content>\n                    \u20101 synthesis in other cell types, also reversed the ammonia\u2010induced\n                    <jats:styled-content style=\"fixed-case\">TSP<\/jats:styled-content>\n                    \u20101 reduction. Likewise, we found a significant decline in\n                    <jats:styled-content style=\"fixed-case\">TSP<\/jats:styled-content>\n                    \u20101 level in cortical astrocytes, as well as a reduction in synaptophysin content\n                    <jats:italic>in vivo<\/jats:italic>\n                    in a rat model of\n                    <jats:styled-content style=\"fixed-case\">CHE<\/jats:styled-content>\n                    . These findings suggest that\n                    <jats:styled-content style=\"fixed-case\">TSP<\/jats:styled-content>\n                    \u20101 may represent an important therapeutic target for\n                    <jats:styled-content style=\"fixed-case\">CHE<\/jats:styled-content>\n                    .\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc12810-fig-0009-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>\n                  <jats:p>Defective release of astrocytic factors may impair synaptic integrity in chronic hepatic encephalopathy. We found a reduction in the release of the astrocytic matricellular proteins thrombospondin\u20101 (TSP\u20101) in ammonia\u2010treated astrocytes; such reduction was associated with a decrease in synaptic proteins caused by conditioned media from ammonia\u2010treated astrocytes. Exposure of neurons to CM from ammonia\u2010treated astrocytes, in which TSP\u20101 is over\u2010expressed, reversed (by approx 75%) the reduction in synaptic proteins. NF\u2010kB\u00a0=\u00a0nuclear factor kappa B; PSD95\u00a0=\u00a0post\u2010synaptic density protein 95; ONS\u00a0=\u00a0oxidative\/nitrative stress.<\/jats:p>","DOI":"10.1111\/jnc.12810","type":"journal-article","created":{"date-parts":[[2014,7,4]],"date-time":"2014-07-04T10:21:03Z","timestamp":1404469263000},"page":"333-347","source":"Crossref","is-referenced-by-count":58,"title":["Decreased astrocytic thrombospondin\u20101 secretion after chronic ammonia treatment reduces the level of synaptic proteins:\n                    <i>in vitro<\/i>\n                    and\n                    <i>in vivo<\/i>\n                    studies"],"prefix":"10.1111","volume":"131","author":[{"given":"Arumugam R.","family":"Jayakumar","sequence":"first","affiliation":[{"name":"Laboratory of Neuropathology Veterans Affairs Medical Center Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao Y.","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin M.","family":"Curtis","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Center and Research Service Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Ruiz\u2010Cordero","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagarajarao","family":"Shamaladevi","sequence":"additional","affiliation":[{"name":"Department of Urology University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Missa","family":"Abuzamel","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Johnstone","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropathology Veterans Affairs Medical Center Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Gaidosh","sequence":"additional","affiliation":[{"name":"Bascom Palmer Eye Institute University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kakulavarapu V.","family":"Rama Rao","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropathology Veterans Affairs Medical Center Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Norenberg","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropathology Veterans Affairs Medical Center Miami Florida USA"},{"name":"Department of Pathology University of Miami School of Medicine Miami Florida USA"},{"name":"Departments of Biochemistry &amp; Molecular Biology University of Miami School of Medicine Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,8]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1824"},{"key":"e_1_2_7_3_1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1523\/JNEUROSCI.15-01-00511.1995","article-title":"Overexpression of synaptophysin enhances neurotransmitter secretion at Xenopus neuromuscular synapses","volume":"15","author":"Alder J.","year":"1995","journal-title":"J. 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