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Article: The mechanism of CaMK2α-MCU-mitochondrial oxidative stress in bupivacaine-induced neurotoxicity

TitleThe mechanism of CaMK2α-MCU-mitochondrial oxidative stress in bupivacaine-induced neurotoxicity
Authors
KeywordsCaMK2α
MCU
Mitochondrial oxidative stress
Bupivacaine
Neurotoxicity
Issue Date2020
PublisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/freeradbiomed
Citation
Free Radical Biology & Medicine, 2020, v. 152, p. 363-374 How to Cite?
AbstractCa2+/calmodulin dependent protein kinase2α (CaMK2α) is a serine/threonine protein kinase in neurons and leads to neuronal injury when it is activated abnormally. Bupivacaine, a local anesthetic commonly used in regional nerve block, could induce neurotoxicity via apoptotic injury. Whether or not CaMK2α is involved in bupivacaine-induced neurotoxicity and it is regulated remains unclear. In this study, bupivacaine was administered for intrathecal injection in C57BL/6 mice for building vivo injury model and was used to culture human neuroblastoma (SH-SY5Y) cells for building vitro injury model. The results showed that bupivacaine induced mitochondrial oxidative stress and neurons apoptotic injury, promoted phosphorylation of CaMK2α and cAMP-response element binding protein (CREB), and elevated mitochondrial Ca2+ uniporter (MCU) expression. Furthermore, it induced CaMK2α phosphorylation at Thr286 which phosphorylated CREB at Ser133 and up-regulated MCU transcriptional expression. Inhibition of CaMK2α-MCU signaling with knock-down of CaMK2α and MCU or with inhibitors (KN93 and Ru360) significantly mitigated bupivacaine-induced neurotoxic injury. Over-expression of CaMK2α significantly enhanced above oxidative injury. Activated MCU with agonist (spermine) reversed protective effect of siCaMK2α on bupivacaine-induced mitochondrial oxidative stress. Our data revealed that CaMK2α-MCU-mitochondrial oxidative stress pathway is a major mechanism whereby bupivacaine induces neurotoxicity and inhibition of above signaling could be a therapeutic strategy in the treatment of bupivacaine-induced neurotoxicity.
Persistent Identifierhttp://hdl.handle.net/10722/293257
ISSN
2019 Impact Factor: 6.17
2015 SCImago Journal Rankings: 2.468
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, Z-
dc.contributor.authorZhao, W-
dc.contributor.authorYuan, P-
dc.contributor.authorZhu, P-
dc.contributor.authorFan, K-
dc.contributor.authorXia, Z-
dc.contributor.authorXu, S-
dc.date.accessioned2020-11-23T08:14:07Z-
dc.date.available2020-11-23T08:14:07Z-
dc.date.issued2020-
dc.identifier.citationFree Radical Biology & Medicine, 2020, v. 152, p. 363-374-
dc.identifier.issn0891-5849-
dc.identifier.urihttp://hdl.handle.net/10722/293257-
dc.description.abstractCa2+/calmodulin dependent protein kinase2α (CaMK2α) is a serine/threonine protein kinase in neurons and leads to neuronal injury when it is activated abnormally. Bupivacaine, a local anesthetic commonly used in regional nerve block, could induce neurotoxicity via apoptotic injury. Whether or not CaMK2α is involved in bupivacaine-induced neurotoxicity and it is regulated remains unclear. In this study, bupivacaine was administered for intrathecal injection in C57BL/6 mice for building vivo injury model and was used to culture human neuroblastoma (SH-SY5Y) cells for building vitro injury model. The results showed that bupivacaine induced mitochondrial oxidative stress and neurons apoptotic injury, promoted phosphorylation of CaMK2α and cAMP-response element binding protein (CREB), and elevated mitochondrial Ca2+ uniporter (MCU) expression. Furthermore, it induced CaMK2α phosphorylation at Thr286 which phosphorylated CREB at Ser133 and up-regulated MCU transcriptional expression. Inhibition of CaMK2α-MCU signaling with knock-down of CaMK2α and MCU or with inhibitors (KN93 and Ru360) significantly mitigated bupivacaine-induced neurotoxic injury. Over-expression of CaMK2α significantly enhanced above oxidative injury. Activated MCU with agonist (spermine) reversed protective effect of siCaMK2α on bupivacaine-induced mitochondrial oxidative stress. Our data revealed that CaMK2α-MCU-mitochondrial oxidative stress pathway is a major mechanism whereby bupivacaine induces neurotoxicity and inhibition of above signaling could be a therapeutic strategy in the treatment of bupivacaine-induced neurotoxicity.-
dc.languageeng-
dc.publisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/freeradbiomed-
dc.relation.ispartofFree Radical Biology & Medicine-
dc.subjectCaMK2α-
dc.subjectMCU-
dc.subjectMitochondrial oxidative stress-
dc.subjectBupivacaine-
dc.subjectNeurotoxicity-
dc.titleThe mechanism of CaMK2α-MCU-mitochondrial oxidative stress in bupivacaine-induced neurotoxicity-
dc.typeArticle-
dc.identifier.emailXia, Z: zyxia@hkucc.hku.hk-
dc.identifier.authorityXia, Z=rp00532-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.freeradbiomed.2020.04.002-
dc.identifier.pmid32275945-
dc.identifier.scopuseid_2-s2.0-85083009208-
dc.identifier.hkuros319783-
dc.identifier.volume152-
dc.identifier.spage363-
dc.identifier.epage374-
dc.identifier.isiWOS:000542949700005-
dc.publisher.placeUnited States-
dc.identifier.issnl0891-5849-

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