PMID- 12065628
OWN - NLM
STAT- MEDLINE
DCOM- 20020712
LR  - 20190630
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 81
IP  - 4
DP  - 2002 May
TI  - Protection against 3,4-methylenedioxymethamphetamine-induced neurodegeneration 
      produced by glutathione depletion in rats is mediated by attenuation of 
      hyperthermia.
PG  - 686-95
AB  - 3,4-Methylenedioxymethamphetamine (MDMA) administration produces neurotoxic 
      degeneration of serotonin terminals in rat brain. These effects occur only after 
      systemic administration and not after central injection, suggesting that 
      peripheral metabolism, possibly hepatic, is required for toxicity. Glutathione is 
      one of the principal cellular defence mechanisms, but conjugation with 
      glutathione can, on some occasions, increase the reactivity of certain molecules. 
      Previous studies have shown that central administration of glutathione adducts of 
      a MDMA metabolite produces a neurotoxicity profile similar to that of systemic 
      MDMA. In the present study, depletion of peripheral (hepatic) glutathione by 43% 
      with dl-buthionine-(S,R)-sulfoximine (an inhibitor of glutathione synthesis) did 
      not attenuate MDMA-induced neurotoxicity as indicated by the 34% loss of [(3) 
      H]paroxetine binding to the serotonin uptake sites in Dark Agouti rats treated 
      with the inhibitor. However, a more profound depletion (92%) of glutathione by 
      diethylmaleate (direct conjugation) administration significantly reduced the 
      serotonergic neurotoxicity produced by MDMA. This depletion protocol also 
      attenuated the hyperthermic response to MDMA. A combination protocol utilising 
      both buthionine-(S,R)-sulfoximine and diethylmaleate that did not alter the 
      hyperthermic response of the rats given MDMA also failed to attenuate the 
      neurotoxicity. These findings indicate that glutathione depletion does not offer 
      specific protection against MDMA-induced serotonin neurotoxicity in Dark Agouti 
      rats.
FAU - O'Shea, Esther
AU  - O'Shea E
AD  - School of Biomedical Sciences, Queen's Medical Centre, Nottingham, UK. 
      estheros@farm.ucm.es
FAU - Easton, N
AU  - Easton N
FAU - Fry, J R
AU  - Fry JR
FAU - Green, A R
AU  - Green AR
FAU - Marsden, C A
AU  - Marsden CA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Maleates)
RN  - 333DO1RDJY (Serotonin)
RN  - 41VRH5220H (Paroxetine)
RN  - 5072-26-4 (Buthionine Sulfoximine)
RN  - 54-16-0 (Hydroxyindoleacetic Acid)
RN  - G81WQB56OL (diethyl maleate)
RN  - GAN16C9B8O (Glutathione)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Animals
MH  - Brain/drug effects/metabolism/pathology
MH  - Brain Chemistry
MH  - Buthionine Sulfoximine/pharmacology
MH  - Drug Therapy, Combination
MH  - Fever/chemically induced/drug therapy/*physiopathology
MH  - Glutathione/analysis/deficiency/*metabolism
MH  - Hydroxyindoleacetic Acid/analysis/metabolism
MH  - Liver/chemistry/drug effects/metabolism
MH  - Male
MH  - Maleates/pharmacology
MH  - *N-Methyl-3,4-methylenedioxyamphetamine
MH  - Neurodegenerative Diseases/chemically induced/drug therapy/*physiopathology
MH  - Paroxetine/pharmacokinetics
MH  - Rats
MH  - Rats, Inbred Strains
MH  - Serotonin/analysis/metabolism
MH  - Treatment Outcome
EDAT- 2002/06/18 10:00
MHDA- 2002/07/13 10:01
CRDT- 2002/06/18 10:00
PHST- 2002/06/18 10:00 [pubmed]
PHST- 2002/07/13 10:01 [medline]
PHST- 2002/06/18 10:00 [entrez]
AID - 10.1046/j.1471-4159.2002.00844.x [doi]
PST - ppublish
SO  - J Neurochem. 2002 May;81(4):686-95. doi: 10.1046/j.1471-4159.2002.00844.x.