Differential effects of fluoxetine and imipramine on the phosphorylation of the transcription factor CREB and cell-viability.
It has been shown that antidepressants increase the expression of CREB (cAMP-response-element-binding-protein) and BDNF (brain derived neurotrophic factor) in vivo. Apparently inconsistent to these survival-promoting properties for many years antidepressants are known to induce apoptosis in various cell types in vitro. In the present study we evaluated if the antidepressants imipramine and fluoxetine are capable to influence the translational expression and phosphorylation of CREB (pCREB) in cells known to be apoptosis-inducible by antidepressants. We therefore used jurkat cells and quantified apoptosis via propidiumiodid-staining and FACS-analysis. CREB-expression and -phosphorylation was quantified via western blot. Both antidepressants induced apoptosis within 24 h. Fluoxetin starts to induce significant apoptosis at a concentration of 20 microM, whereas imipramine at 100 microM. At these concentrations both antidepressants also increased the phosphorylation of CREB within 6 h. But even in concentrations to low to induce apoptosis both antidepressants still increased CREB-phosphorylation. Treating cells with lowest concentrations only imipramine revealed an increase of CREB-phosphorylation after long-time treatment over 3 weeks. In all experiments overall CREB-expression remained unchanged. In conclusion our experiments indicate that antidepressants are capable to increase CREB-phosphorylation without induction of apoptosis depending on concentration and duration of treatment. We further assume that antidepressants induce CREB-phosphorylation via signal transduction pathways that are different from those inducing apoptosis.
Koch
Jakob M
JM
Department of Psychiatry, Christian-Albrecht-University Kiel, 24105 Kiel, Germany. jkoch@psychiatry,uni-kiel.de
Kell
Susanne
S
Aldenhoff
Josef B
JB
D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D007099:Imipramine / Q000494:pharmacology*; D019169:Jurkat Cells; D010766:Phosphorylation / Q000187:drug effects; D013997:Time Factors
D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D017362:Cyclic AMP Response Element-Binding Protein; D005473:Fluoxetine; D007099:Imipramine