PMID- 11752059
OWN - NLM
STAT- MEDLINE
DCOM- 20020116
LR  - 20190630
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 79
IP  - 6
DP  - 2001 Dec
TI  - Glutathione depletion switches nitric oxide neurotrophic effects to cell death in 
      midbrain cultures: implications for Parkinson's disease.
PG  - 1183-95
AB  - Nitric oxide (NO) exerts neurotrophic and neurotoxic effects on dopamine (DA) 
      function in primary midbrain cultures. We investigate herein the role of 
      glutathione (GSH) homeostasis in the neurotrophic effects of NO. Fetal midbrain 
      cultures were pretreated with GSH synthesis inhibitor, 
      L-buthionine-(S,R)-sulfoximine (BSO), 24 h before the addition of NO donors 
      (diethylamine/nitric oxide-complexed sodium and S-nitroso-N-acetylpenicillamine) 
      at doses tested previously as neurotrophic. Under these conditions, the 
      neurotrophic effects of NO disappeared and turned on highly toxic. Reduction of 
      GSH levels to 50% of baseline induced cell death in response to neurotrophic 
      doses of NO. Soluble guanylate cyclase (sGC) and cyclic GMP-dependent protein 
      kinase (PKG) inhibitors protected from cell death for up to 10 h after NO 
      addition; the antioxidant ascorbic acid also protected from cell death but its 
      efficacy decreased when it was added after NO treatment (40% protection 2 h after 
      NO addition). The pattern of cell death was characterized by an increase in 
      chromatin condensed cells with no DNA fragmentation and with breakdown of 
      plasmatic membrane. The inhibition of RNA and protein synthesis and of caspase 
      activity also protected from cell death. This study shows that alterations in GSH 
      levels change the neurotrophic effects of NO in midbrain cultures into 
      neurotoxic. Under these conditions, NO triggers a programmed cell death with 
      markers of both apoptosis and necrosis characterized by an early step of free 
      radicals production followed by a late requirement for signalling on the 
      sGC/cGMP/PKG pathway.
FAU - Canals, S
AU  - Canals S
AD  - Departamento de Investigacion, Servicio de Neurobiologia, Hospital Ramon y Cajal, 
      Madrid, Spain.
FAU - Casarejos, M J
AU  - Casarejos MJ
FAU - de Bernardo, S
AU  - de Bernardo S
FAU - Rodriguez-Martin, E
AU  - Rodriguez-Martin E
FAU - Mena, M A
AU  - Mena MA
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 (Alkaloids)
RN  - 0 (Aminoquinolines)
RN  - 0 (Antioxidants)
RN  - 0 (Carbazoles)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Free Radicals)
RN  - 0 (Hydrazines)
RN  - 0 (Indoles)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nitric Oxide Donors)
RN  - 0 (Nitrogen Oxides)
RN  - 0 (Nucleic Acid Synthesis Inhibitors)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (S-nitro-N-acetylpenicillamine)
RN  - 126643-37-6 (KT 5823)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 5072-26-4 (Buthionine Sulfoximine)
RN  - 86831-65-4 (1,1-diethyl-2-hydroxy-2-nitrosohydrazine)
RN  - 91300-60-6 (6-anilino-5,8-quinolinedione)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
RN  - EC 4.6.1.2 (Guanylate Cyclase)
RN  - EC 6.3.2.3 (Glutathione Synthase)
RN  - GAN16C9B8O (Glutathione)
RN  - GNN1DV99GX (Penicillamine)
RN  - PQ6CK8PD0R (Ascorbic Acid)
RN  - T42P99266K (Methylene Blue)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Alkaloids/pharmacology
MH  - Aminoquinolines/pharmacology
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - Apoptosis/*drug effects
MH  - Ascorbic Acid/pharmacology
MH  - Buthionine Sulfoximine/pharmacology
MH  - *Carbazoles
MH  - Cell Division/drug effects
MH  - Cells, Cultured/drug effects/metabolism
MH  - Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors/physiology
MH  - Dopamine/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Free Radicals
MH  - Glutathione/deficiency/*physiology
MH  - Glutathione Synthase/antagonists & inhibitors
MH  - Guanylate Cyclase/antagonists & inhibitors/physiology
MH  - Homeostasis
MH  - Hydrazines
MH  - *Indoles
MH  - Mesencephalon/*cytology/embryology
MH  - Methylene Blue/pharmacology
MH  - Nerve Tissue Proteins/analysis/biosynthesis/physiology
MH  - Neurons/cytology/drug effects/*metabolism
MH  - Nitric Oxide/*physiology
MH  - Nitric Oxide Donors/pharmacology
MH  - Nitrogen Oxides
MH  - Nucleic Acid Synthesis Inhibitors/pharmacology
MH  - Parkinson Disease/*metabolism
MH  - Penicillamine/*analogs & derivatives/pharmacology
MH  - Protein Synthesis Inhibitors/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tyrosine 3-Monooxygenase/analysis/biosynthesis
EDAT- 2001/12/26 10:00
MHDA- 2002/01/17 10:01
CRDT- 2001/12/26 10:00
PHST- 2001/12/26 10:00 [pubmed]
PHST- 2002/01/17 10:01 [medline]
PHST- 2001/12/26 10:00 [entrez]
AID - 10.1046/j.1471-4159.2001.00635.x [doi]
PST - ppublish
SO  - J Neurochem. 2001 Dec;79(6):1183-95. doi: 10.1046/j.1471-4159.2001.00635.x.