Methadone directly impairs central nervous system cells in vitro

De Gregorio, Cristian; Gallardo, Javiera; Berríos, Pablo; Handy, Álex; Santapau, Daniela; González, Antonia; Ezquer, Marcelo; Morales, Paola; Luarte, Alejandro; Corvalán, Daniela; Wyneken, Úrsula; Ezquer, Fernando

Publication:
Methadone directly impairs central nervous system cells in vitro

dc.contributor.author	De Gregorio, Cristian
dc.contributor.author	Gallardo, Javiera
dc.contributor.author	Berríos, Pablo
dc.contributor.author	Handy, Álex
dc.contributor.author	Santapau, Daniela
dc.contributor.author	González, Antonia
dc.contributor.author	Ezquer, Marcelo
dc.contributor.author	Morales, Paola
dc.contributor.author	Luarte, Alejandro
dc.contributor.author	Corvalán, Daniela
dc.contributor.author	Wyneken, Úrsula
dc.contributor.author	Ezquer, Fernando
dc.date.accessioned	2025-01-13T16:15:07Z
dc.date.available	2025-01-13T16:15:07Z
dc.date.issued	2024
dc.description.abstract	Methadone is a synthetic long-acting opioid that is increasingly used in the replacement therapy of opioid-addicted patients, including pregnant women. However, methadone therapy in this population poses challenges, as it induces cognitive and behavioral impairments in infants exposed to this opioid during prenatal development. In animal models, prenatal methadone exposure results in detrimental consequences to the central nervous system, such as: (i) increased neuronal apoptosis; (ii) disruption of oligodendrocyte maturation and increased apoptosis and (iii) increased microglia and astrocyte activation. However, it remains unclear whether these deleterious effects result from a direct effect of methadone on brain cells. Therefore, our goal was to uncover the impact of methadone on single brain cell types in vitro. Primary cultures of rat neurons, oligodendrocytes, microglia, and astrocytes were treated for three days with 10 µM methadone to emulate a chronic administration. Apoptotic neurons were identified by cleaved caspase-3 detection, and synaptic density was assessed by the juxtaposition of presynaptic and postsynaptic markers. Apoptosis of oligodendrocyte precursors was determined by cleaved caspase-3 detection. Oligodendrocyte myelination was assessed by immunofluorescence, while microglia and astrocyte proinflammatory activation were assessed by both immunofluorescence and RT-qPCR. Methadone treatment increased neuronal apoptosis and reduced synaptic density. Furthermore, it led to increased oligodendrocyte apoptosis and a reduction in the myelinating capacity of these cells, and promoted the proinflammatory activation of microglia and astrocytes. We showed that methadone, the most widely used drug in opioid replacement therapy for pregnant women with opioid addiction, directly impairs brain cells in vitro, highlighting the need for developing alternative therapies to address opioid addiction in this population.
dc.description.version	Versión Publicada
dc.identifier.citation	De Gregorio C, Gallardo J, Berríos-Cárcamo P, Handy Á, Santapau D, González-Madrid A, Ezquer M, Morales P, Luarte A, Corvalán D, Wyneken Ú, Ezquer F. Methadone directly impairs central nervous system cells in vitro. Sci Rep. 2024 Jul 23;14(1):16978. doi: 10.1038/s41598-024-67860-7
dc.identifier.doi	https://doi.org/10.1038/s41598-024-67860-7
dc.identifier.uri	https://hdl.handle.net/11447/9629
dc.language.iso	en
dc.subject	Brain damage
dc.subject	Methadone
dc.subject	Neurodegeneration
dc.subject	Neuroinflammation
dc.subject	Opioid addiction
dc.subject	Opioid substitution therapy
dc.title	Methadone directly impairs central nervous system cells in vitro
dc.type	Article
dcterms.accessRights	Acceso Abierto
dcterms.source	Scientific reports
dspace.entity.type	Publication
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