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Aged rats are more vulnerable than adolescents to “ecstasy”-induced toxicity

  • Organ Toxicity and Mechanisms
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Abstract

3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a widespread drug of abuse with known neurotoxic properties. The present study aimed to evaluate the differential toxic effects of MDMA in adolescent and aged Wistar rats, using doses pharmacologically comparable to humans. Adolescent (post-natal day 40) (3 × 5 mg/kg, 2 h apart) and aged (mean 20 months old) (2 × 5 mg/kg, 2 h apart) rats received MDMA intraperitoneally. Animals were killed 7 days later, and the frontal cortex, hippocampus, striatum and cerebellum brain areas were dissected, and heart, liver and kidneys were collected. MDMA caused hyperthermia in both treated groups, but aged rats had a more dramatic temperature elevation. MDMA promoted serotonergic neurotoxicity only in the hippocampus of aged, but not in the adolescents’ brain, and did not change the levels of dopamine or serotonin metabolite in the striatum of both groups. Differential responses according to age were also seen regarding brain p-Tau levels, a hallmark of a degenerative brain, since only aged animals had significant increases. MDMA evoked brain oxidative stress in the hippocampus and striatum of aged, and in the hippocampus, frontal cortex, and striatum brain areas of adolescents according to protein carbonylation, but only decreased GSH levels in the hippocampus of aged animals. The brain maturational stage seems crucial for MDMA-evoked serotonergic neurotoxicity. Aged animals were more susceptible to MDMA-induced tissue damage in the heart and kidneys, and both ages had an increase in liver fibrotic tissue content. In conclusion, age is a determinant factor for the toxic events promoted by “ecstasy”. This work demonstrated special susceptibility of aged hippocampus to MDMA neurotoxicity, as well as impressive damage to the heart and kidney tissue following “ecstasy”.

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Abbreviations

5-HIAA:

5-Hydroxyindoleacetic acid

5-HT:

Serotonin

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

ATP:

Adenosine triphosphate

BSA:

Bovine serum albumin

CHAPS:

3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate hydrate

CKMB:

Creatine kinase MB isoenzyme

DA:

Dopamine

DTT:

Dithiothreitol

EDTA:

Ethylenediamine tetraacetic acid

GFAP:

Glial fibrillary acidic protein

GSH:

Reduced glutathione

GSHt:

Total glutathione

GSSG:

Oxidized glutathione

HEPES:

4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid

5-HIAA:

5-Hydroxyindoleacetic acid

HNE:

Hydroxynonenal

HPLC:

High-performance liquid chromatography

i.p.:

Intraperitoneal

MDMA:

3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”)

NA:

Noradrenaline

PBS:

Phosphate-buffered saline

OD:

Optic density

PMSF:

Phenylmethanesulfonyl fluoride

PND:

Post-natal day

p-Tau:

Phosphorylated Tau

ROS:

Reactive oxygen species

SERT:

Serotonin transporter

SDS:

Sodium dodecyl sulphate

TCA:

Trichloroacetic acid

TPH:

Tryptophan hydroxylase

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Acknowledgements

We greatly acknowledge Dr. ª Bárbara Oliveira of ICBAS-UP animal house facility, and Dr.a Laura Pereira of FFUP biochemistry for their technical assistance. This work was supported by the Fundação para a Ciência e Tecnologia (FCT)—Project PTDC/SAU-FCF/102958/2008—QREN initiative with EU/FEDER financing through under the frame of ‘‘Programa Operacional Temático Factores de Competitividade (COMPETE) do Quadro Comunitário de Apoio III’’ and ‘‘Fundo Comunitário Europeu (FEDER)’’ (FCOMP-01-0124-FEDER-011079). It was also supported by FEDER funds through the COMPETE and by national funds by the Fundação para a Ciência e Tecnologia (FCT) within the Project “PTDC/DTP-FTO/1489/2014—POCI-01-0145-FEDER-016537”. This work also received financial support from the European Union (FEDER funds POCI/01/0145/FEDER/007728) and National Funds (FCT/MEC, Fundação para a Ciência e a Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/MULTI/04378/2013. Additionally, supported by project NORTE-01-0145-FEDER-000024, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement (DESignBIOtecHealth—New Technologies for three Health Challenges of Modern Societies: Diabetes, Drug Abuse and Kidney Diseases), through the European Regional Development Fund (ERDF). VM Costa and DJ Barbosa acknowledge FCT for their post-doc (SFRH/BPD/110001/2015) and PhD grants (SFRH/BD/64939/2009), respectively.

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Correspondence to J. P. Capela.

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Parts of this work have been presented orally at the Portuguese Pharmacology Society annual meeting, and in the form of an abstract and poster at the Congress of the European Societies of Toxicology (Eurotox). Some results included in this article were incorporated in Armanda Gomes Master thesis entitled “Brain and Peripheral Organ Toxicity of “Ecstasy” in Adolescent Rats in Human Relevant Doses” printed last September 2014. The thesis document is available online at the university of Porto repository: https://repositorio-aberto.up.pt/bitstream/10216/76843/2/32960.pdf.

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Feio-Azevedo, R., Costa, V.M., Barbosa, D.J. et al. Aged rats are more vulnerable than adolescents to “ecstasy”-induced toxicity. Arch Toxicol 92, 2275–2295 (2018). https://doi.org/10.1007/s00204-018-2226-8

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  • DOI: https://doi.org/10.1007/s00204-018-2226-8

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