PMID- 24299738
OWN - NLM
STAT- MEDLINE
DCOM- 20141014
LR  - 20211021
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 138
IP  - 1
DP  - 2014 Mar
TI  - Glial cell response to 3,4-(+/-)-methylenedioxymethamphetamine and its 
      metabolites.
PG  - 130-8
LID - 10.1093/toxsci/kft275 [doi]
AB  - 3,4-(+/-)-Methylenedioxymethamphetamine (MDMA) and 
      3,4-(+/-)-methylenedioxyamphetamine (MDA), a primary metabolite of MDMA, are 
      phenylethylamine derivatives that cause serotonergic neurotoxicity. Although 
      several phenylethylamine derivatives activate microglia, little is known about 
      the effects of MDMA on glial cells, and evidence of MDMA-induced microglial 
      activation remains ambiguous. We initially determined microglial occupancy status 
      of the parietal cortex in rats at various time points following a single 
      neurotoxic dose of MDMA (20mg/kg, SC). A biphasic microglial response to MDMA was 
      observed, with peak microglial occupancy occurring 12- and 72-h post-MDMA 
      administration. Because direct injection of MDMA into the brain does not produce 
      neurotoxicity, the glial response to MDMA metabolites was subsequently examined 
      in vivo and in vitro. Rats were treated with MDA (20mg/kg, SC) followed by ex 
      vivo biopsy culture to determine the activation of quiescent microglia. A 
      reactive microglial response was observed 72 h after MDA administration that 
      subsided by 7 days. In contrast, intracerebroventricular (ICV) administration of 
      MDA failed to produce a microglial response. However, thioether metabolites of 
      MDA derived from alpha-methyldopamine (alpha-MeDA) elicited a robust microglial response 
      following icv injection. We subsequently determined the direct effects of various 
      MDMA metabolites on primary cultures of E18 hippocampal mixed glial and neuronal 
      cells. 5-(Glutathion-S-yl)-alpha-MeDA, 2,5-bis-(glutathion-S-yl)-alpha-MeDA, and 
      5-(N-acetylcystein-S-yl)-alpha-MeDA all stimulated the proliferation of glial 
      fibrillary acidic protein-positive astrocytes at a dose of 10 microM. The findings 
      indicate that glial cells are activated in response to MDMA/MDA and support a 
      role for thioether metabolites of alpha-MeDA in the neurotoxicity.
FAU - Herndon, Joseph M
AU  - Herndon JM
AD  - Department of Pharmacology and Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, Arizona 85721.
FAU - Cholanians, Aram B
AU  - Cholanians AB
FAU - Lau, Serrine S
AU  - Lau SS
FAU - Monks, Terrence J
AU  - Monks TJ
LA  - eng
GR  - P30 ES006694/ES/NIEHS NIH HHS/United States
GR  - DA023525/DA/NIDA NIH HHS/United States
GR  - T32 ES007091/ES/NIEHS NIH HHS/United States
GR  - 5T32ES007091/ES/NIEHS NIH HHS/United States
GR  - R01 DA023525/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20131203
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (Sulfides)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/metabolism/*toxicity
MH  - Animals
MH  - Astrocytes/drug effects/metabolism/pathology
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Coculture Techniques
MH  - Dose-Response Relationship, Drug
MH  - Glial Fibrillary Acidic Protein/metabolism
MH  - Hippocampus/drug effects/metabolism/pathology
MH  - Immunohistochemistry
MH  - Injections, Intraventricular
MH  - Male
MH  - Microglia/*drug effects/metabolism/pathology
MH  - N-Methyl-3,4-methylenedioxyamphetamine/metabolism/*toxicity
MH  - Neurons/drug effects/metabolism/pathology
MH  - Neurotoxicity Syndromes/etiology/*metabolism/pathology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sulfides
PMC - PMC3930364
OTO - NOTNLM
OT  - 3,4-(+/-)-methylenedioxymethamphetamine
OT  - metabolites
OT  - microglial activation.
EDAT- 2013/12/05 06:00
MHDA- 2014/10/15 06:00
PMCR- 2015/03/01
CRDT- 2013/12/05 06:00
PHST- 2013/12/05 06:00 [entrez]
PHST- 2013/12/05 06:00 [pubmed]
PHST- 2014/10/15 06:00 [medline]
PHST- 2015/03/01 00:00 [pmc-release]
AID - kft275 [pii]
AID - 10.1093/toxsci/kft275 [doi]
PST - ppublish
SO  - Toxicol Sci. 2014 Mar;138(1):130-8. doi: 10.1093/toxsci/kft275. Epub 2013 Dec 3.