{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T16:10:40Z","timestamp":1790525440389,"version":"4.1.0"},"reference-count":65,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2008,12,2]],"date-time":"2008-12-02T00:00:00Z","timestamp":1228176000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Glia"],"published-print":{"date-parts":[[2009,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The clearance of extracellular glutamate is mainly mediated by pH\u2010 and sodium\u2010dependent transport into astrocytes. During hepatic encephalopathy (HE), however, elevated extracellular glutamate concentrations are observed. The primary candidate responsible for the toxic effects observed during HE is ammonium (NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>\/NH<jats:sub>3<\/jats:sub>). Here, we examined the effects of NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>\/NH<jats:sub>3<\/jats:sub>on steady\u2010state intracellular pH (pH<jats:sub>i<\/jats:sub>) and sodium concentration ([Na<jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>) in cultured astrocytes in two different age groups. Moreover, we assessed the influence of NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>\/NH<jats:sub>3<\/jats:sub>on glutamate transporter activity by measuring<jats:sc>D<\/jats:sc>\u2010aspartate\u2010induced pH<jats:sub>i<\/jats:sub>and [Na<jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>transients. In 20\u201334 days<jats:italic>in vitro<\/jats:italic>(DIV) astrocytes, NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>\/NH<jats:sub>3<\/jats:sub>decreased steady\u2010state pH<jats:sub>i<\/jats:sub>by 0.19 pH units and increased [Na<jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>by 21 mM.<jats:sc>D<\/jats:sc>\u2010Aspartate\u2010induced pH<jats:sub>i<\/jats:sub>and [Na<jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>transients were reduced by 80\u201390% in the presence of NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>\/NH<jats:sub>3<\/jats:sub>, indicating a dramatic reduction of glutamate uptake activity. In 9\u201316 DIV astrocytes, in contrast, pH<jats:sub>i<\/jats:sub>and [Na<jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>were minimally affected by NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>\/NH<jats:sub>3<\/jats:sub>, and<jats:sc>D<\/jats:sc>\u2010aspartate\u2010induced pH<jats:sub>i<\/jats:sub>and [Na<jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>transients were reduced by only 30\u201340%. Next we determined the contribution of Na<jats:sup>+<\/jats:sup>, K<jats:sup>+<\/jats:sup>, Cl<jats:sup>\u2212<\/jats:sup>\u2010cotransport (NKCC). Immunocytochemical stainings indicated an increased expression of NKCC1 in 20\u201334 DIV astrocytes. Moreover, inhibition of NKCC with bumetanide prevented NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>\/NH<jats:sub>3<\/jats:sub>\u2010evoked changes in steady\u2010state pH<jats:sub>i<\/jats:sub>and [Na<jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>and attenuated the reduction of<jats:sc>D<\/jats:sc>\u2010aspartate\u2010induced pH<jats:sub>i<\/jats:sub>and [Na<jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>transients by NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>\/NH<jats:sub>3<\/jats:sub>to 30% in 20\u201334 DIV astrocytes. Our results suggest that NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>\/NH<jats:sub>3<\/jats:sub>decreases steady\u2010state pH<jats:sub>i<\/jats:sub>and increases steady\u2010state [Na<jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>in astrocytes by an age\u2010dependent activation of NKCC. These NH<jats:sub>4<\/jats:sub><jats:sup>+<\/jats:sup>\/NH<jats:sub>3<\/jats:sub>\u2010evoked changes in the transmembrane pH and sodium gradients directly reduce glutamate transport activity, and may, thus, contribute to elevated extracellular glutamate levels observed during HE. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/glia.20817","type":"journal-article","created":{"date-parts":[[2008,12,2]],"date-time":"2008-12-02T22:28:02Z","timestamp":1228256882000},"page":"921-934","source":"Crossref","is-referenced-by-count":76,"title":["Ammonium\u2010evoked alterations in intracellular sodium and pH reduce glial glutamate transport activity"],"prefix":"10.1002","volume":"57","author":[{"given":"Tony","family":"Kelly","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl 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