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Excessive intracellular [Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      accumulation weakens \u03b3\u2010aminobutyric acid (GABA) compensatory effects. Sub\u2010anesthetic dose of propofol protected the brain against ischemia\u2013hypoxia, which was abolished by blocking Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      efflux transporter K\n                      <jats:sup>+<\/jats:sup>\n                      \/Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      cotransporter 2 (KCC2). We aimed to determine whether low\u2010dose anesthetic combined with [Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      regulators could restore the compensatory GABAergic system and improve cognitive function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Chronic cerebral hypoxia (CCH) model was established by bilateral carotid artery ligation in aged rats. Sub\u2010dose of anesthetics (propofol and sevoflurane) with or without KCC2 agonist N\u2010ethylmaleimide (NEM) or Na\n                      <jats:sup>+<\/jats:sup>\n                      \/K\n                      <jats:sup>+<\/jats:sup>\n                      \/Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      cotransporter 1 (NKCC1) antagonist bumetanide (BTN) was administered systemically 30\u2009days post\u2010surgery. Primary rat hippocampal neuronal cultures were subjected to hypoxic injury with or without drug treatment. Memory function, hippocampal neuronal survival, GABAergic system functioning, and brain\u2010derived neurotrophic factor (BDNF) expressions were evaluated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sub\u2010anesthetic dose of combined propofol (1.2\u2009\u03bcg\u2009mL\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) and sevoflurane [0.7 MAC (minimum alveolar concentration)] did not aggravate the hypoxic brain injury in rats or cell damage in neuronal cultures. Adding either BTN or NEM protected against hypoxic injury, associated with improved cognitive function in vivo, less intracellular accumulation of [Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      , reduced cell death, restored GABAergic compensation, and increased BDNF expression both in vivo and in vitro.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Sub\u2010anesthetic dose of propofol and sevoflurane is a recommended anesthesia regimen in at\u2010risk patients. Restoration of [Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      homeostasis and GABAergic could further reduce the brain damage caused by ischemia\u2013hypoxia.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.14379","type":"journal-article","created":{"date-parts":[[2023,8,6]],"date-time":"2023-08-06T23:16:04Z","timestamp":1691363764000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Sub\u2010dose anesthetics combined with chloride regulators protect the brain against chronic ischemia\u2013hypoxia injury"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7299-3668","authenticated-orcid":false,"given":"Chenyi","family":"Yang","sequence":"first","affiliation":[{"name":"Nankai University  Tianjin China"},{"name":"Nankai University Affinity the 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