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However, endogenous choline and <jats:styled-content style=\"fixed-case\">ACh<\/jats:styled-content> have not been regarded as potent neuroprotective agents because physiological levels of choline\/<jats:styled-content style=\"fixed-case\">ACh<\/jats:styled-content> do not produce neuroprotective levels of \u03b17 activation. This limitation may be overcome by the use of type\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> positive allosteric modulators (<jats:styled-content style=\"fixed-case\">PAMs<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>) of \u03b17 n<jats:styled-content style=\"fixed-case\">AChR<\/jats:styled-content>s, such as 1\u2010(5\u2010chloro\u20102,4\u2010dimethoxyphenyl)\u20103\u2010(5\u2010methylisoxazol\u20103\u2010yl)\u2010urea (<jats:styled-content style=\"fixed-case\">PNU<\/jats:styled-content>\u2010120596). This proof\u2010of\u2010concept study presents a novel neuroprotective paradigm that converts endogenous choline\/<jats:styled-content style=\"fixed-case\">ACh<\/jats:styled-content> into potent neuroprotective agents in cerebral ischaemia by inhibiting \u03b17 nAChR desensitization using <jats:styled-content style=\"fixed-case\">PNU<\/jats:styled-content>\u2010120596.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>An electrophysiological <jats:italic>ex vivo<\/jats:italic> cell injury assay (to quantify the susceptibility of hippocampal neurons to acute injury by complete oxygen and glucose deprivation; <jats:styled-content style=\"fixed-case\">COGD<\/jats:styled-content>) and an <jats:italic>in vivo<\/jats:italic> middle cerebral artery occlusion model of ischaemia were used in rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Choline (20\u2013200\u2009\u03bcM) in the presence, but not absence of 1\u2009\u03bcM <jats:styled-content style=\"fixed-case\">PNU<\/jats:styled-content>\u2010120596 significantly delayed anoxic depolarization\/injury of hippocampal <jats:styled-content style=\"fixed-case\">CA<\/jats:styled-content>1 pyramidal neurons, but not <jats:styled-content style=\"fixed-case\">CA<\/jats:styled-content>1 stratum radiatum interneurons, subjected to <jats:styled-content style=\"fixed-case\">COGD<\/jats:styled-content> in acute hippocampal slices and these effects were blocked by 20\u2009nM methyllycaconitine, a selective \u03b17 antagonist, thus, activation of \u03b17 nAChRs was required. <jats:styled-content style=\"fixed-case\">PNU<\/jats:styled-content>\u2010120596 alone was ineffective <jats:italic>ex vivo<\/jats:italic>. In <jats:italic>in vivo<\/jats:italic> experiments, both pre\u2010 and post\u2010ischaemia treatments with <jats:styled-content style=\"fixed-case\">PNU<\/jats:styled-content>\u2010120596 (30\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>, s.c. and 1\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>, i.v., respectively) significantly reduced the cortical\/subcortical infarct volume caused by transient focal cerebral ischaemia. <jats:styled-content style=\"fixed-case\">PNU<\/jats:styled-content>\u2010120596 (1\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>, i.v., 30\u2009min post\u2010ischaemia) remained neuroprotective in rats subjected to a choline\u2010deficient diet for 14\u2009days prior to experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>PNU\u2010120596 and possibly other <jats:styled-content style=\"fixed-case\">PAMs<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> significantly improved neuronal survival in cerebral ischaemia by augmenting neuroprotective effects of endogenous choline\/<jats:styled-content style=\"fixed-case\">ACh<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12247","type":"journal-article","created":{"date-parts":[[2013,5,28]],"date-time":"2013-05-28T11:29:27Z","timestamp":1369740567000},"page":"1862-1878","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["A positive allosteric modulator of \u03b17 n<scp>AChR<\/scp>s augments neuroprotective effects of endogenous nicotinic agonists in cerebral ischaemia"],"prefix":"10.1111","volume":"169","author":[{"given":"Bopanna I","family":"Kalappa","sequence":"first","affiliation":[{"name":"Department of Pharmacology Southern Illinois University School of Medicine  Springfield IL 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