{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T02:55:55Z","timestamp":1791168955768,"version":"4.1.0"},"reference-count":39,"publisher":"S. Karger AG","issue":"1","license":[{"start":{"date-parts":[[2012,5,24]],"date-time":"2012-05-24T00:00:00Z","timestamp":1337817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2012,5,24]],"date-time":"2012-05-24T00:00:00Z","timestamp":1337817600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurodegener Dis"],"published-print":{"date-parts":[[2013]]},"abstract":"<b><i>Background:<\/i><\/b> Inhibition of mitochondrial function occurs in many neurodegenerative diseases, and inhibitors of mitochondrial complexes I and II are used to model them. The complex II inhibitor, 3-nitroproprionic acid (3-NPA), kills the striatal neurons susceptible in Huntington\u2019s disease. The complex I inhibitor N-methyl-4-phenylpyridium (MPP<sup>+<\/sup>) and 6-hydroxydopamine (6-OHDA) are used to model Parkinson\u2019s disease. Zinc (Zn<sup>2+)<\/sup> accumulates after 3-NPA, 6-OHDA and MPP<sup>+<\/sup> in situ or in vivo. <b><i>Objective:<\/i><\/b> We will investigate the role of Zn<sup>2+<\/sup> neurotoxicity in 3-NPA, 6-OHDA and MPP<sup>+<\/sup>. <b><i>Methods:<\/i><\/b> Murine striatal\/midbrain tyrosine hydroxylase positive, or near-pure cortical neuronal cultures, or animals were exposed to 3-NPA or MPP<sup>+<\/sup> and 6-OHDA with or without neuroprotective compounds. Intracellular zinc ([Zn<sup>2+<\/sup>]<sub>i<\/sub>), nicotinamide adenine dinucleotide (NAD<sup>+<\/sup>), NADH, glycolytic intermediates and neurotoxicity were measured. <b><i>Results:<\/i><\/b> We showed that compounds or genetics which restore NAD<sup>+<\/sup> and attenuate Zn<sup>2+<\/sup> neurotoxicity (pyruvate, nicotinamide, NAD<sup>+<\/sup>, increased NAD<sup>+<\/sup> synthesis, sirtuin inhibition or Zn<sup>2+<\/sup> chelation) attenuated the neuronal death induced by these toxins. The increase in [Zn<sup>2+<\/sup>]<sub>i<\/sub> preceded a reduction in the NAD<sup>+<\/sup>\/NADH ratio that caused a reversible glycolytic inhibition. Pyruvate, nicotinamide and NAD<sup>+<\/sup> reversed the reductions in the NAD<sup>+<\/sup>\/NADH ratio, glycolysis and neuronal death after challenge with 3-NPA, 6-OHDA or MPP<sup>+<\/sup>, as was previously shown for exogenous Zn<sup>2+<\/sup>. To test efficacy in vivo, we injected 3-NPA into the striatum of rats and systemically into mice, with or without pyruvate. We observed early striatal Zn<sup>2+<\/sup> fluorescence, and pyruvate significantly attenuated the 3-NPA-induced lesion and restored behavioral scores. <b><i>Conclusions:<\/i><\/b> Together, these studies suggest that Zn<sup>2+<\/sup> accumulation caused by MPP<sup>+<\/sup> and 3-NPA is a novel preventable mechanism of the resultant neurotoxicity.<\/jats:p>","DOI":"10.1159\/000336558","type":"journal-article","created":{"date-parts":[[2012,5,24]],"date-time":"2012-05-24T08:00:36Z","timestamp":1337846436000},"page":"49-58","source":"Crossref","is-referenced-by-count":45,"title":["Mitochondrial Inhibitor Models of Huntington\u2019s Disease and Parkinson\u2019s Disease Induce Zinc Accumulation and Are Attenuated by Inhibition of Zinc Neurotoxicity in vitro or in vivo"],"prefix":"10.1159","volume":"11","author":[{"given":"Christian T.","family":"Sheline","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiao","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai-Li","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"127","published-online":{"date-parts":[[2012,5,24]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1016%2FS0166-2236%2800%2901584-8"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1016%2FS0166-2236%2899%2901415-0"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1002%2Fana.410410514"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1023%2FB%3ANERE.0000014824.04728.dd"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1097%2F00004647-200207000-00005"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.neulet.2004.08.027"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1002%2Fana.410320616"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1212%2FWNL.47.6_Suppl_3.161S"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1007%2FBF00978370"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1002%2F%28SICI%291097-4547%2819990701%2957%3A1%3C86%3A%3AAID-JNR9%3E3.0.CO%3B2-E"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1016%2FS0006-8993%2801%2902551-3"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.brainres.2009.06.046"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.neuro.2005.04.007"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1111%2Fj.1460-9568.2010.07372.x"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1006%2Fnbdi.1998.0177"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1111%2Fj.1460-9568.2006.05110.x"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.neuroscience.2006.02.019"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.expneurol.2004.07.012"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1111%2Fj.1471-4159.2005.03253.x"},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.1097%2F00019052-199412000-00012"},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.1196%2Fannals.1427.008"},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.1196%2Fannals.1427.023"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1196%2Fannals.1427.018"},{"key":"ref24","doi-asserted-by":"publisher","DOI":"10.1111%2Fj.1471-4159.2009.06074.x"},{"key":"ref25","doi-asserted-by":"publisher","DOI":"10.1097%2FWCO.0b013e3282ef58cd"},{"key":"ref26","doi-asserted-by":"publisher","DOI":"10.1074%2Fjbc.M401135200"},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.1016%2F0014-4886%2895%2990033-0"},{"key":"ref28","doi-asserted-by":"publisher","DOI":"10.1016%2FS0304-3940%2897%2900827-6"},{"key":"ref29","doi-asserted-by":"publisher","DOI":"10.1111%2Fj.1749-6632.1999.tb07998.x"},{"key":"ref30","doi-asserted-by":"publisher","DOI":"10.1073%2Fpnas.96.10.5774"},{"key":"ref31","doi-asserted-by":"publisher","DOI":"10.1126%2Fscience.1102497"},{"key":"ref32","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.expneurol.2006.05.017"},{"key":"ref33","doi-asserted-by":"publisher","DOI":"10.1523%2FJNEUROSCI.0525-08.2008"},{"key":"ref34","doi-asserted-by":"publisher","DOI":"10.1073%2Fpnas.96.4.1716"},{"key":"ref35","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.brainres.2003.12.034"},{"key":"ref36","doi-asserted-by":"publisher","DOI":"10.1016%2FS0161-813X%2802%2900110-9"},{"key":"ref37","doi-asserted-by":"publisher","DOI":"10.1016%2FS0304-3940%2802%2901327-7"},{"key":"ref38","doi-asserted-by":"publisher","DOI":"10.1002%2Fana.10276"},{"key":"ref39","doi-asserted-by":"publisher","DOI":"10.1002%2Fana.20047"}],"container-title":["Neurodegenerative 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