Neuronal cell death induced by antidepressants: lack of correlation with Egr-1, NF-kappa B and extracellular signal-regulated protein kinase activation.
The tricyclic antidepressants (TCA) amitriptyline and desipramine and the serotonin reuptake inhibitor fluoxetine induce, at microM 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-kappa 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-kappa B activity by elevation of the intracellular cAMP concentration or by retroviral driven expression of the non-degradable superrepressor I kappa B alpha S32A/S36A demonstrated that the elevation of NF-kappa B activity by amitriptyline, desipramine and fluoxetine is not an integral part of the apoptotic signaling cascade triggered by these compounds.
Bartholomä
Pia
P
Department of Medical Biochemistry and Molecular Biology, University of Saarland Medical Center, D-66421 Homburg, Germany.
Erlandsson
Nina
N
Kaufmann
Katrin
K
Rössler
Oliver G
OG
Baumann
Bernd
B
Wirth
Thomas
T
Giehl
Klaus M
KM
Thiel
Gerald
G
D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D016923:Cell Death; D000242:Cyclic AMP / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D051766:Early Growth Response Protein 1; D005473:Fluoxetine / Q000494:pharmacology; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins; D008246:Lysophospholipids; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010084:Oxidation-Reduction; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis*
D000928:Antidepressive Agents; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins; D008246:Lysophospholipids; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D014157:Transcription Factors; D005473:Fluoxetine; D000072000:NF-KappaB Inhibitor alpha; D000639:Amitriptyline; C060506:sphingosine 1-phosphate; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D013110:Sphingosine; D003891:Desipramine