PMID- 15081269
OWN - NLM
STAT- MEDLINE
DCOM- 20040519
LR  - 20131121
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 196
IP  - 2
DP  - 2004 Apr 15
TI  - Neurotoxicity of amphetamine derivatives is mediated by caspase pathway 
      activation in rat cerebellar granule cells.
PG  - 223-34
AB  - The neurotoxic action of the abuse drugs methamphetamine (METH) and 
      3,4-methylenedioxymethamphetamine (MDMA) on cerebellar granule neurones (CGNs) 
      culture was examined. Treatment for 48 h with METH or MDMA (1-5 mM) induced a 
      higher decrease in viability than 24 h treatment. z.VAD.fmk (100 microM) but not 
      MK-801 nor NBQX recovered control viability values. In both cases, cell death was 
      characterised as apoptotic rather than necrotic by morphology cell observation. 
      Apoptosis measured by flow cytometry indicated an increase in the hypodiploid 
      population after 48 h treatment with METH and MDMA. Apoptosis was reverted by the 
      presence of z.VAD.fmk (100 microM) but not by 10 microM MK-801 or NBQX. Similar 
      results were obtained by analysing nuclear chromatine condensation. These results 
      ruled out excitotoxic participation in amphetamine derivative-induced 
      neurotoxicity in CGNs. Participation of radical oxygen species (ROS) was 
      evaluated using alpha-tocopherol (1-15 microM) and cytometric studies. The 
      co-treatment with 4 mM METH or MDMA for 48 h partially reverted neurotoxic action 
      and apoptotic features, indicating ROS implication in CGNs death by amphetamine 
      derivatives. Alteration of mitochondrial function induced cytochrome C (Cyt C) 
      release after 48-h treatment with METH and MDMA (4 mM). There was also indication 
      of caspase-3-like activation, measured by immunoanalysis and biochemically. 
      Finally, neurodegenerative action caused by amphetamine derivatives may be 
      prevented by using caspase inhibitors.
FAU - Jimenez, Andres
AU  - Jimenez A
AD  - Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia, Universitat de 
      Barcelona, Barcelona 08028, Spain.
FAU - Jorda, Elvira G
AU  - Jorda EG
FAU - Verdaguer, Ester
AU  - Verdaguer E
FAU - Pubill, David
AU  - Pubill D
FAU - Sureda, Francesc X
AU  - Sureda FX
FAU - Canudas, Anna M
AU  - Canudas AM
FAU - Escubedo, Elena
AU  - Escubedo E
FAU - Camarasa, Jordi
AU  - Camarasa J
FAU - Camins, Antoni
AU  - Camins A
FAU - Pallas, Merce
AU  - Pallas M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Quinoxalines)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
RN  - 118876-58-7 (2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline)
RN  - 44RAL3456C (Methamphetamine)
RN  - 6LR8C1B66Q (Dizocilpine Maleate)
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 3.4.22.- (Casp3 protein, rat)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
RN  - H4N855PNZ1 (alpha-Tocopherol)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Amino Acid Chloromethyl Ketones/*pharmacology
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Caspase 3
MH  - Caspases/*metabolism
MH  - Cerebellum/cytology/*drug effects/*enzymology/metabolism
MH  - Cytochromes c/metabolism
MH  - Dizocilpine Maleate/pharmacology
MH  - Drug Interactions
MH  - Enzyme Activation
MH  - Flow Cytometry
MH  - Methamphetamine/*antagonists & inhibitors/*toxicity
MH  - Microscopy, Fluorescence
MH  - Microscopy, Phase-Contrast
MH  - Mitochondria/enzymology/metabolism
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*antagonists & inhibitors/*toxicity
MH  - Neurons/cytology/drug effects/enzymology/metabolism
MH  - Neuroprotective Agents/*pharmacology
MH  - Quinoxalines/pharmacology
MH  - Rats
MH  - Reactive Oxygen Species/metabolism
MH  - alpha-Tocopherol/pharmacology
EDAT- 2004/04/15 05:00
MHDA- 2004/05/20 05:00
CRDT- 2004/04/15 05:00
PHST- 2003/05/29 00:00 [received]
PHST- 2003/12/17 00:00 [accepted]
PHST- 2004/04/15 05:00 [pubmed]
PHST- 2004/05/20 05:00 [medline]
PHST- 2004/04/15 05:00 [entrez]
AID - S0041008X04000080 [pii]
AID - 10.1016/j.taap.2003.12.017 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2004 Apr 15;196(2):223-34. doi: 
      10.1016/j.taap.2003.12.017.