Because of increasing evidence against the "catecholamine deficiency hypothesis" to explain patho-mechanism of depression, an alternative hypothesis on the mechanism of antidepressants, the "plasticity hypothesis", was proposed [17
In this study we analyzed the transcription of growth factors in cell culture systems. SY5Y cells were pre-treated by the phorbolester PMA to induce differentiation into neuronal cells [15
]. PMA changed transcription levels of several growth factors massively, but we found that antidepressant drugs counteracted these PMA-induced changes.
Recent post mortem studies in suicide subjects revealed significantly lower levels of BDNF in the prefrontal cortex and hippocampus. Authors of several studies provided evidence that BDNF could be involved in depressive behaviour [21
]. Because growth factors induce the formation of neurite-like processes [22
], we concluded from our microscopic images that the growth factors were also expressed in SY5Y cells. However, we couldn't confirm the expression for every factor (data not shown). The morphological changes provide some evidence that the modulation (up and down regulation) of several growth factors is responsible for the observed effect. A direct correlation with a single growth factor, like BDNF, can not be causal [24
]. All four classes of antidepressants, tested in our study, antagonistically reversed strong up or down regulation of growth factors, induced by PMA in cultured SY5Y cells [15
The up-regulation of BDNF and Creb in vivo
seem to be a central part of the antidepressant properties of antidepressants [17
], however, there is few evidence for the variation of other growth factors so far. Different modes of stress can induce either selective up and down regulation of BDNF splice variants [26
] Earlier gene transcription studies in in vivo
systems had shown that several genes were either up- or down-regulated by antidepressant treatment [27
]. These and our observations assign a role of modulators to antidepressants, rather than pure stimulators of growth factor transcription.
We found that if transcription of a factor increased during the cultivation period, this increase was attenuated by antidepressants. On the other hand, antidepressants increased the transcription of factors that became down regulated upon PMA-treatment. The antagonistic regulation of growth factors was a common property of all antidepressant classes; however, there were differences in kinetics and specificity. Amitriptyline, for example, did not prevent the PMA-induced decrease of bFGF and CNTF, but it worked antagonistically for all other factors. In general, it favoured more down regulation than other drugs. Reboxetine worked in an exactly opposite way on the transcription of growth factors, by strongly increasing down regulated factors and modestly reducing up regulated factors. Fluoxetine and tranylcypromine represented classes with similar modulator properties, but with different kinetics. Fluoxetine has been shown to increase the expression of bFGF in rats [29
]. This was observed in our experiments too.
In a pilot experiment PC-12 cells were treated with rTMS. These cells were chosen, because they are electrical excitable, which made them potentially susceptible for repetitive magnetic stimulation. These cells showed an increase in BDNF, TGFβ2 and tyrosine hydroxylase (figure ). In contrast to PC-12 cells, SY5Y cells showed a decrease of BDNF (figure ). BDNF mRNA was elevated in all treated samples, compared to controls; however, statistical significance was not reached, due to small sample numbers. It has been shown previously that rTMS and antidepressants acted in a similar way in rat hippocampus [30
] and humans [31
]. We could only partly support this hypothesis.