ScienceDirect - Biochemical Pharmacology : Neuronal cell death induced by antidepressants: lack of correlation with Egr-1, NF-B and extracellular signal-regulated protein kinase activation

Pia Bartholomä^a^,¹, Nina Erlandsson^a^,¹, Katrin Kaufmann^a, Oliver G. Rössler^a, Bernd Baumann^b, Thomas Wirth^b, Klaus M. Giehl^c 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.

Abstract

The tricyclic antidepressants (TCA) amitriptyline and desipramine and the serotonin reuptake inhibitor fluoxetine induce, at small mu, Greek 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- small kappa, Greek 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- small kappa, Greek B activity by elevation of the intracellular cAMP concentration or by retroviral driven expression of the non-degradable superrepressor IB small alpha, Greek S32A/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- small kappa, Greek B; Sphingosine-1-phosphate

Abbreviations: dbcAMP, N,2'-O-dibutyryladenosine-3:5-cyclic monophosphate; Egr-1, early growth response 1; ERK, extracellular signal-regulated protein kinase; IBMX, isobutyl-1-methylxanthine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; TCA, tricyclic antidepressants; TUNEL, terminal deoxynucleotidyl transferase fluorescein-dUTP 3'-end labeling.

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