{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:10:57Z","timestamp":1784956257251,"version":"3.55.0"},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2006,4,5]],"date-time":"2006-04-05T00:00:00Z","timestamp":1144195200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2006,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Developing oligodendrocytes (OL precursors, pre\u2010OLs) express \u03b1\u2010amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazolepropionic acid (AMPA) subtype glutamate receptors (AMPARs) and are highly vulnerable to hypoxic\u2010ischemic or oxygen\u2010glucose deprivation (OGD)\u2010induced excitotoxic injury, yet the mechanisms of injury remain unclear. Here we investigated the role of glutamate accumulation and mitochondrial function in OGD\u2010induced pre\u2010OL toxicity <jats:italic>in vitro<\/jats:italic>. Bulk glutamate concentration in the culture medium did not increase during OGD and OGD\u2010conditioned medium did not transfer toxicity to na\u00efve cells. Facilitation of glutamate diffusion by constant agitation of the culture reduced, while inhibition of glutamate diffusion by increasing medium viscosity with dextran enhanced, OGD\u2010induced pre\u2010OL injury. Depletion of extracellular glutamate by the glutamate scavenging system, glutamate\u2010pyruvate transaminase plus pyruvate, attenuated pre\u2010OL injury during OGD. Together these data suggest that local glutamate accumulation is critical for OGD toxicity. Interestingly, under normoxic conditions, addition of glutamate to pre\u2010OLs did not cause receptor\u2010mediated toxicity, but the toxicity could be unmasked by mitochondrial impairment with mitochondrial toxins. Furthermore, OGD caused mitochondrial potential collapse that was independent of AMPAR activation, and OGD toxicity was enhanced by mitochondrial toxins. These data demonstrate that pre\u2010OL excitotoxicity is exacerbated by mitochondrial dysfunction during OGD. Overall, our results indicate that OGD\u2010induced pre\u2010OL injury is a novel form of excitotoxicity caused by the combination of local glutamate accumulation that occurs without an increase in bulk glutamate concentration and mitochondrial dysfunction. Therapeutic strategies targeting local glutamate concentration and mitochondrial injury during hypoxia\u2010ischemia may be relevant to human disorders associated with pre\u2010OL excitotoxicity.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2006.03861.x","type":"journal-article","created":{"date-parts":[[2006,4,5]],"date-time":"2006-04-05T12:09:48Z","timestamp":1144238988000},"page":"213-222","source":"Crossref","is-referenced-by-count":51,"title":["Oligodendrocyte excitotoxicity determined by local glutamate accumulation and mitochondrial function"],"prefix":"10.1111","volume":"98","author":[{"given":"Wenbin","family":"Deng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Rosenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Volpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances E.","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,5,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-04-01302.2001"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2004.03616.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2001.81.2.871"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1984.tb05396.x"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(88)90162-6"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/neu.480230915"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-813X(02)00196-1"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1136624100"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307850101"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-01-00034.2000"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0477-04.2004"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-24-09235.2000"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.00866.x"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/1098-1136(200008)31:2<165::AID-GLIA80>3.0.CO;2-#"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.10082"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199403033300907"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.00981.x"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(99)00009-1"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-200201000-00007"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(00)01746-X"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(02)01847-2"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.16.8830"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.85.3.890"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0398-291"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1042\/bss0660055"},{"key":"e_1_2_7_27_1","first-page":"790","article-title":"Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention","volume":"13","author":"Oka A.","year":"1993","journal-title":"J. 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