PMID- 28122248
OWN - NLM
STAT- MEDLINE
DCOM- 20171212
LR  - 20181203
IS  - 1872-9754 (Electronic)
IS  - 0197-0186 (Linking)
VI  - 105
DP  - 2017 May
TI  - MDMA-induced neurotoxicity of serotonin neurons involves autophagy and 
      rilmenidine is protective against its pathobiology.
PG  - 80-90
LID - S0197-0186(17)30030-X [pii]
LID - 10.1016/j.neuint.2017.01.010 [doi]
AB  - Toxicity of 3,4-methylenedioxymethamphetamine (MDMA) towards biogenic amine 
      neurons is well documented and in primate brain predominantly affects serotonin 
      (5-HT) neurons. MDMA induces damage of 5-HT axons and nerve fibres and 
      intracytoplasmic inclusions. Whilst its pathobiology involves 
      mitochondrially-mediated oxidative stress, we hypothesised MDMA possessed the 
      capacity to activate autophagy, a proteostatic mechanism for degradation of 
      cellular debris. We established a culture of ventral pons from embryonic murine 
      brain enriched in 5-HT neurons to explore mechanisms of MDMA neurotoxicity and 
      recruitment of autophagy, and evaluated possible neuroprotective actions of the 
      clinically approved agent rilmenidine. MDMA (100 muM-1 mM) reduced cell viability, 
      like rapamycin (RM) and hydrogen peroxide (H(2)O(2)), in a concentration- and 
      time-dependent manner. Immunocytochemistry revealed dieback of 5-HT arbour: 
      MDMA-induced injury was slower than for RM and H(2)O(2), neuritic blebbing 
      occurred at 48 and 72 h and Hoechst labelling revealed nuclear fragmentation with 
      100 muM MDMA. MDMA effected concentration-dependent inhibition of [(3)H]5-HT 
      uptake with 500 muM MDMA totally blocking transport. Western immunoblotting for 
      microtubule associated protein light chain 3 (LC3) revealed autophagosome 
      formation after treatment with MDMA. Confocal analyses and immunocytochemistry 
      for 5-HT, Hoechst and LC3 confirmed MDMA induced autophagy with abundant 
      LC3-positive puncta within 5-HT neurons. Rilmenidine (1 muM) protected against 
      MDMA-induced injury and image analysis showed full preservation of 5-HT arbours. 
      MDMA had no effect on GABA neurons, indicating specificity of action at 5-HT 
      neurons. MDMA-induced neurotoxicity involves autophagy induction in 5-HT neurons, 
      and rilmenidine via beneficial actions against toxic intracellular events 
      represents a potential treatment for its pathobiology in sustained usage.
CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
FAU - Mercer, Linda D
AU  - Mercer LD
AD  - Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 
      Parkville, Victoria 3010, Australia.
FAU - Higgins, Gavin C
AU  - Higgins GC
AD  - Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 
      Parkville, Victoria 3010, Australia.
FAU - Lau, Chew L
AU  - Lau CL
AD  - Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 
      Parkville, Victoria 3010, Australia.
FAU - Lawrence, Andrew J
AU  - Lawrence AJ
AD  - Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 
      Parkville, Victoria 3010, Australia.
FAU - Beart, Philip M
AU  - Beart PM
AD  - Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 
      Parkville, Victoria 3010, Australia. Electronic address: 
      philip.beart@florey.edu.au.
LA  - eng
PT  - Journal Article
DEP - 20170123
PL  - England
TA  - Neurochem Int
JT  - Neurochemistry international
JID - 8006959
RN  - 0 (Adrenergic alpha-Agonists)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Oxazoles)
RN  - 0 (Serotonin Agents)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - P67IM25ID8 (Rilmenidine)
SB  - IM
MH  - Adrenergic alpha-Agonists/pharmacology
MH  - Animals
MH  - Autophagy/*drug effects/physiology
MH  - Cell Survival/drug effects/physiology
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
MH  - Neuroprotective Agents/*pharmacology
MH  - Oxazoles/*pharmacology
MH  - Pregnancy
MH  - Rilmenidine
MH  - Serotonergic Neurons/*drug effects/*pathology/physiology
MH  - Serotonin Agents/toxicity
OTO - NOTNLM
OT  - MDMA
OT  - Neuroprotection
OT  - Programmed cell death
OT  - Rilmenidine
OT  - Serotonin neuron
OT  - mTOR-independent autophagy
EDAT- 2017/01/26 06:00
MHDA- 2017/12/13 06:00
CRDT- 2017/01/26 06:00
PHST- 2017/01/20 00:00 [received]
PHST- 2017/01/20 00:00 [accepted]
PHST- 2017/01/26 06:00 [pubmed]
PHST- 2017/12/13 06:00 [medline]
PHST- 2017/01/26 06:00 [entrez]
AID - S0197-0186(17)30030-X [pii]
AID - 10.1016/j.neuint.2017.01.010 [doi]
PST - ppublish
SO  - Neurochem Int. 2017 May;105:80-90. doi: 10.1016/j.neuint.2017.01.010. Epub 2017 
      Jan 23.