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Neuronal cell death induced by antidepressants: lack of correlation with
Egr-1, NF-B and
extracellular signal-regulated protein kinase activation
Oliver G. Rösslera,
Klaus M. Giehlc
and Gerald Thiel, , a
a Department of Medical Biochemistry and Molecular Biology, University of Saarland Medical Center, D-66421 Homburg, Germany
b Department of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany
c Department of Anatomy, University of Saarland Medical Center, D-66421 Homburg, Germany
Received 27 November 2001; accepted 28 January 2002. Available online 13 March 2002.
Pia Bartholomäa, 1, Nina Erlandssona, 1, Katrin Kaufmanna, Oliver G. Rösslera, Bernd Baumannb, Thomas Wirthb, Klaus M. Giehlc and Gerald Thiel, , a
The tricyclic antidepressants (TCA) amitriptyline and desipramine and the serotonin reuptake inhibitor fluoxetine induce, at M concentrations, cell death in HT22 immortalized hippocampal neurons and PC12 pheochromocytoma cells. Here, we show that these neurotoxic effects are accompanied by a selective activation of extracellular signal-regulated protein kinase (ERK), the biosynthesis of the transcription factor Egr-1 and an increase in the transcriptional activity of NF-B. However, an impairment of both ERK activation and Egr-1 biosynthesis by the MAP kinase kinase-1 (MEK-1) inhibitor PD98059 did not block cell death. Moreover, stimulation of ERK phosphorylation and Egr-1 biosynthesis by sphingosine-1-phosphate did not induce cell death, indicating that stimulation of the ERK signaling pathway and Egr-1 biosynthesis are not required for neuronal cell death induced by antidepressants. Likewise, attenuation of antidepressant-induced NF-B activity by elevation of the intracellular cAMP concentration or by retroviral driven expression of the non-degradable superrepressor IBS32A/S36A demonstrated that the elevation of NF-B activity by amitriptyline, desipramine and fluoxetine is not an integral part of the apoptotic signaling cascade triggered by these compounds.
Author Keywords: Antidepressants; Egr-1; Extracellular signal-regulated kinase; Neuronal cell death; NF-B; Sphingosine-1-phosphate
N,2'-O-dibutyryladenosine-3:5-cyclic monophosphate; Egr-1, early
growth response 1; ERK, extracellular signal-regulated protein kinase; IBMX,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; TCA, tricyclic
antidepressants; TUNEL, terminal deoxynucleotidyl transferase fluorescein-dUTP
1 These authors contributed equally to the study.
Corresponding author. Tel.: +49-6841-1626504; fax: +49-6841-1626500; email: firstname.lastname@example.org
Volume 63, Issue 8 , 15 April 2002, Pages 1507-1516
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