PMID- 27861613
OWN - NLM
STAT- MEDLINE
DCOM- 20170626
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 11
DP  - 2016
TI  - Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse 
      P19 Embryonal Carcinoma Cells.
PG  - e0166750
LID - 10.1371/journal.pone.0166750 [doi]
LID - e0166750
AB  - 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a commonly abused 
      recreational drug that causes neurotoxic effects in both humans and animals. The 
      mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent 
      and needs to be further investigated on the cellular level. In this study, the 
      effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells 
      have been examined. MDMA produces a concentration-, time- and 
      temperature-dependent toxicity in differentiated P19 neurons, as measured by 
      intracellular MTT reduction and extracellular LDH activity assays. The 
      P19-derived neurons express both the serotonin reuptake transporter (SERT), that 
      is functionally active, and the serotonin metabolizing enzyme monoamine oxidase A 
      (MAO-A). The involvement of these proteins in the MDMA-induced toxicity was 
      investigated by a pharmacological approach. The MAO inhibitors clorgyline and 
      deprenyl, and the SERT inhibitor fluoxetine, per se or in combination, were not 
      able to mimic the toxic effects of MDMA in the P19-derived neurons or block the 
      MDMA-induced cell toxicity. Oxidative stress has been implicated in MDMA-induced 
      neurotoxicity, but pre-treatment with the antioxidants alpha-tocopherol or 
      N-acetylcysteine did not reveal any protective effects in the P19 neurons. 
      Involvement of mitochondria in the MDMA-induced cytotoxicity was also examined, 
      but MDMA did not alter the mitochondrial membrane potential (DeltaPsim) in the P19 
      neurons. We conclude that MDMA produce a concentration-, time- and 
      temperature-dependent neurotoxicity and our results suggest that the mechanism 
      behind MDMA-induced toxicity in mouse-derived neurons do not involve the 
      serotonergic system, oxidative stress or mitochondrial dysfunction.
FAU - Popova, Dina
AU  - Popova D
AD  - Department of Pharmacology and Clinical Neuroscience, Umea University, Umea, 
      Sweden.
FAU - Forsblad, Andreas
AU  - Forsblad A
AD  - Department of Pharmacology and Clinical Neuroscience, Umea University, Umea, 
      Sweden.
FAU - Hashemian, Sanaz
AU  - Hashemian S
AD  - Department of Pharmacology and Clinical Neuroscience, Umea University, Umea, 
      Sweden.
FAU - Jacobsson, Stig O P
AU  - Jacobsson SO
AUID- ORCID: 0000-0001-9740-8499
AD  - Department of Pharmacology and Clinical Neuroscience, Umea University, Umea, 
      Sweden.
LA  - eng
PT  - Journal Article
DEP - 20161118
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 01K63SUP8D (Fluoxetine)
RN  - 2K1V7GP655 (Selegiline)
RN  - EC 1.4.3.4 (Monoamine Oxidase)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - LYJ16FZU9Q (Clorgyline)
SB  - IM
MH  - Animals
MH  - Cell Differentiation/drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Clorgyline/pharmacology
MH  - Embryonal Carcinoma Stem Cells
MH  - Fluoxetine/pharmacology
MH  - Gene Expression
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mice
MH  - Monoamine Oxidase/genetics/metabolism
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacology
MH  - Neurons/*drug effects/*metabolism
MH  - Selegiline/pharmacology
MH  - Serotonin Plasma Membrane Transport Proteins/genetics/metabolism
PMC - PMC5115802
COIS- The authors have declared that no competing interests exist.
EDAT- 2016/11/20 06:00
MHDA- 2017/06/27 06:00
PMCR- 2016/11/18
CRDT- 2016/11/19 06:00
PHST- 2016/02/05 00:00 [received]
PHST- 2016/11/03 00:00 [accepted]
PHST- 2016/11/19 06:00 [entrez]
PHST- 2016/11/20 06:00 [pubmed]
PHST- 2017/06/27 06:00 [medline]
PHST- 2016/11/18 00:00 [pmc-release]
AID - PONE-D-16-05346 [pii]
AID - 10.1371/journal.pone.0166750 [doi]
PST - epublish
SO  - PLoS One. 2016 Nov 18;11(11):e0166750. doi: 10.1371/journal.pone.0166750. 
      eCollection 2016.