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In cerebral ischaemia, loss of cellular ion homeostasis due to Na<jats:sup>+<\/jats:sup> channel activation, together with increased reactive oxygen species (ROS) production, are thought to contribute to neuronal death. Since neuronal death in the penumbra of the ischaemic lesion is suggested to occur by apoptosis, we investigated the ability of AM\u201036, antioxidants and Na<jats:sup>+<\/jats:sup> channel antagonists to inhibit toxicity induced by the neurotoxin, veratridine in cultured cerebellar granule cells (CGC's).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Veratridine (10\u2003\u2013\u2003300\u2003\u03bc<jats:sc>M<\/jats:sc>) concentration\u2010dependently reduced cell viability of cultured CGC's. Under the experimental conditions employed, cell death induced by veratridine (100\u2003\u03bc<jats:sc>M<\/jats:sc>) possessed the characteristics of apoptosis as assessed by morphology, TUNEL staining and DNA laddering on agarose gels.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Neurotoxicity and apoptosis induced by veratridine (100\u2003\u03bc<jats:sc>M<\/jats:sc>) were inhibited to a maximum of 50% by the antioxidants, U74500A (0.1\u2003\u2013\u200310\u2003\u03bc<jats:sc>M<\/jats:sc>) and U83836E (0.03\u2003\u2013\u200310\u2003\u03bc<jats:sc>M<\/jats:sc>), and to a maximum of 30% by the Na<jats:sup>+<\/jats:sup> channel blocker, dibucaine (0.1\u2003\u2013\u2003100\u2003\u03bc<jats:sc>M<\/jats:sc>). In contrast, AM\u201036 (0.01\u2003\u2013\u200310\u2003\u03bc<jats:sc>M<\/jats:sc>) completely inhibited veratridine\u2010induced toxicity (IC<jats:sub>50<\/jats:sub> 1.7 (1.5\u2003\u2013\u20031.9) \u03bc<jats:sc>M<\/jats:sc>, 95% confidence intervals (CI) in parentheses) and concentration\u2010dependently inhibited apoptosis.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These findings suggest veratridine\u2010induced toxicity and apoptosis are partially mediated by generation of ROS. AM\u201036, which combines both Na<jats:sup>+<\/jats:sup> channel blocking and antioxidant activity, provided superior neuroprotection compared with agents possessing only one of these actions. This bifunctional profile of activity may underlie the potent neuroprotective effects of AM\u201036 recently found in a stroke model in conscious rats.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2001) <jats:bold>132<\/jats:bold>, 1691\u20131698; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0704018\">10.1038\/sj.bjp.0704018<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0704018","type":"journal-article","created":{"date-parts":[[2005,1,28]],"date-time":"2005-01-28T21:23:30Z","timestamp":1106947410000},"page":"1691-1698","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM\u201036, results in profound inhibition of neuronal apoptosis"],"prefix":"10.1111","volume":"132","author":[{"given":"Jennifer K","family":"Callaway","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip M","family":"Beart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bevyn","family":"Jarrott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah F","family":"Giardina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,1,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.16.7162"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.76.1.514"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1056-8719(98)00022-7"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.30.12.2704"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01345257"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.20.040180.000311"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(19980401)52:1<69::AID-JNR7>3.0.CO;2-I"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(98)00123-3"},{"key":"e_1_2_7_10_1","first-page":"21","article-title":"Apoptosis in focal cerebral ischemia","volume":"66","author":"CHOPP M.","year":"1996","journal-title":"Acta. 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