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Methylone and MDPV activate autophagy in human dopaminergic SH-SY5Y cells: a new insight into the context of β-keto amphetamines-related neurotoxicity

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dc.contributor.authorValente, Maria João
dc.contributor.authorAmaral, Cristina
dc.contributor.authorCorreia-da-Silva, Georgina
dc.contributor.authorDuarte, José Alberto
dc.contributor.authorBastos, Maria de Lourdes
dc.contributor.authorCarvalho, Félix
dc.contributor.authorGuedes de Pinho, Paula
dc.contributor.authorCarvalho, Márcia
dc.date.accessioned2021-06-30T11:07:00Z
dc.date.available2021-06-30T11:07:00Z
dc.date.issued2017
dc.description.abstractAutophagy has an essential role in neuronal homeostasis and its dysregulation has been recently linked to neurotoxic effects of a growing list of psychoactive drugs, including amphetamines. However, the role of autophagy in β-keto amphetamine (β-KA) designer drugs-induced neurotoxicity has hitherto not been investigated. In the present study, we show that two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV), elicit morphological changes consistent with autophagy and neurodegeneration, including formation of autophagic vacuoles and neurite retraction in dopaminergic SH-SY5Y cells. Methylone and MDPV prompted the formation of acidic vesicular organelles (AVOs) and lead to increased expression of the autophagy-associated protein LC3-II in a concentration- and time-dependent manner. Electron microscopy confirmed the presence of autophagosomes with typical double membranes and autolysosomes in cells exposed to both β-KA. The autophagic flux was further confirmed using bafilomycin A1, a known inhibitor of the late phase of autophagy. Moreover, we showed that autophagy markers were activated before the triggering of cell death and caspase 3 activation, suggesting that β-KA-induced autophagy precedes apoptotic cell death. To address the role of oxidative stress in autophagy induction, we also investigated the effects of antioxidant treatment with N-acetyl-L-cysteine (NAC) on autophagy and apoptotic markers altered by these drugs. NAC significantly attenuated methylone- and MDPV-induced cell death by completely inhibiting the generation of reactive oxygen and nitrogen species, and hampering both apoptotic and autophagic activity, suggesting that oxidative stress plays an important role in mediating autophagy and apoptosis elicited by these drugs.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1007/s00204-017-1984-zpt_PT
dc.identifier.eissn1432-0738
dc.identifier.issn0340-5761
dc.identifier.urihttp://hdl.handle.net/10284/9981
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringerpt_PT
dc.relationThis work received financial support from the European Union (FEDER funds POCI/01/0145/FEDER/007728) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/MULTI/04378/2013. The study is a result of the project NORTE-01-0145-FEDER-000024, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement (DESignBIO- tecHealth—New Technologies for three Health Challenges of Modern Societies: Diabetes, Drug Abuse and Kidney Diseases), through the European Regional Development Fund (ERDF). M.J.V. and C.A. thank Fundação para a Ciência e Tecnologia (FCT), Portugal, for their PhD (SFRH/BD/89879/2012) and Post-Doc grants (SFRH/ BPD/98304/2013), respectively.pt_PT
dc.subjectβ-Keto amphetaminespt_PT
dc.subjectNeurotoxicitypt_PT
dc.subjectAutophagypt_PT
dc.subjectApoptosispt_PT
dc.subjectOxidative stresspt_PT
dc.titleMethylone and MDPV activate autophagy in human dopaminergic SH-SY5Y cells: a new insight into the context of β-keto amphetamines-related neurotoxicitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage3676pt_PT
oaire.citation.issue11pt_PT
oaire.citation.startPage3663pt_PT
oaire.citation.titleArchives of Toxicologypt_PT
oaire.citation.volume91pt_PT
person.familyNameCarvalho
person.givenNameMarcia
person.identifier2017111
person.identifier.ciencia-id8B10-171E-E63E
person.identifier.orcid0000-0001-9884-4751
person.identifier.ridD-5999-2013
person.identifier.scopus-author-id7201413997
rcaap.rightsclosedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication3837b828-ba57-47f7-a811-cce65e4922c6
relation.isAuthorOfPublication.latestForDiscovery3837b828-ba57-47f7-a811-cce65e4922c6

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