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However, NMDAR antagonists often cause side effects, and identifying more druggable therapeutic targets for NMDAR excitotoxicity is an important goal. Activation of caspases is a downstream effect of excitotoxicity that may be critically involved in NMDAR\u2010mediated cell death. Caspase\u20106 (casp6) in particular has been shown to play a key role in the pathogenesis of stroke, Huntington disease, and Alzheimer disease. Using N\u2010methyl D\u2010aspartate (NMDA)\u2010induced excitotoxic injuries of primary rat neurons, we demonstrate that there is an early increase in caspase profiles after an excitotoxic event at the level of mRNA, protein, and activity. Casp6 is elevated and activated first, followed by caspase\u20108 and caspase\u20103. Similarly, known casp6 substrates huntingtin, as well as novel casp6 substrates serine\/threonine kinase 3 and death domain\u2010associated protein, are cleaved in similar temporal patterns post NMDA. On the basis of these data, we propose that casp6 may be an initiator caspase in apoptotic cascades leading to neuronal death after an excitotoxic event and suggest casp6 as a potential therapeutic target for neurological disorders where NMDAR\u2010mediated excitotoxicity has been shown to play a role.<\/jats:p>","DOI":"10.1002\/jnr.24153","type":"journal-article","created":{"date-parts":[[2017,11,30]],"date-time":"2017-11-30T04:36:41Z","timestamp":1512016601000},"page":"391-406","source":"Crossref","is-referenced-by-count":23,"title":["Activation of caspase\u20106 and cleavage of caspase\u20106 substrates is an early event in NMDA receptor\u2013mediated excitotoxicity"],"prefix":"10.1002","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9780-4731","authenticated-orcid":false,"given":"Kimberly D.","family":"Girling","sequence":"first","affiliation":[{"name":"University of British Columbia, Brain Research Centre &amp; Department of Medicine Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Josee","family":"Demers","sequence":"additional","affiliation":[{"name":"Research Centre on Aging, Department Pharmacology and Physiology, Faculty of Medicine and Health Sciences University of Sherbrooke Sherbrooke Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Laine","sequence":"additional","affiliation":[{"name":"Research Centre on Aging, Department Pharmacology and Physiology, Faculty of Medicine and Health Sciences University of Sherbrooke Sherbrooke Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of British Columbia, Brain Research Centre &amp; Department of Medicine Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Tian","family":"Wang","sequence":"additional","affiliation":[{"name":"University of British Columbia, Brain Research Centre &amp; Department of Medicine Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3722-6241","authenticated-orcid":false,"given":"Rona K.","family":"Graham","sequence":"additional","affiliation":[{"name":"Research Centre on Aging, Department Pharmacology and Physiology, Faculty of Medicine and Health Sciences University of Sherbrooke Sherbrooke Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,11,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072873"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2433"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0698-11.2011"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.060974"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181c1da10"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400733"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-013-1149-z"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1089\/089771503322686166"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-100913-013226"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2008-13101"},{"issue":"3","key":"e_1_2_8_12_1","first-page":"S110","article-title":"Excitotoxicity and nitric oxide in Parkinson's disease pathogenesis","volume":"44","author":"Beal M. 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