The Predominant Protective Effect of Tianeptine Over Other Antidepressants in Models of Neuronal Apoptosis: The Effect Blocked by Inhibitors of MAPK/ERK1/2 and PI3-K/Akt Pathways

Abstract

Tianeptine (Tian) possesses neuroprotective potential, however, little is known about the effect of this drug in models of neuronal apoptosis. In the present study, we aimed (1) to compare the neuroprotective capacities of some antidepressants (ADs) in the models of staurosporine (St)- and doxorubicin (Dox)-evoked cell death, activating the intracellular and the extracellular apoptotic pathway, respectively; (2) to identify the Tian-modulated steps underlying its neuroprotective action; (3) to test the effect of various ADs against Dox-evoked cell damage in glia cells. Primary neuronal and glia cell cultures and retinoic acid-differentiated human neuroblastoma SH-SY5Y (RA-SH-SY5Y) cells were co-treated with imipramine, fluoxetine, citalopram, reboxetine, mirtazapine or Tian and St or Dox. The data showed the predominant neuroprotective effect of Tian over other tested ADs against St- and Dox-induced cell damage in primary neurons and in RA-SH-SY5Y cells. This effect was shown to be caspase-3-independent but connected with attenuation of DNA fragmentation. Moreover, neuroprotection elicited by Tian was blocked by pharmacological inhibitors of MAPK/ERK1/2 and PI3-K/Akt signaling pathways as well by inhibitor of necroptosis, necrostatin-1. Interestingly, the protective effects of all tested ADs were demonstrated in primary glia cells against the Dox-evoked cell damage. The obtained data suggests the glial cells as a common target for protective action of various ADs whereas in relation to neuronal cells only Tian possesses such properties, at least against St- and Dox-induced cell damage. Moreover, this neuroprotective effect of Tian is caspase-3-independent and engages the regulation of survival pathways (MAPK/ERK1/2 and PI3-K/Akt).Electronic supplementary materialThe online version of this article (doi:10.1007/s12640-013-9430-3) contains supplementary material, which is available to authorized users.

Neuroprotective effects of mGluR II and III activators against staurosporine- and doxorubicin-induced cellular injury in SH-SY5Y cells: New evidence for a mechanism involving inhibition of AIF translocation

“…Caspase-3 activity was measured with a fluorometric method employing the fluorogenic substrate, AC-DEVD-AMC as described previously (Jantas et al, 2014a). The UN-and RA-SH-SY5Y cells were treated with mGluR II/III activators and St or Dox for 6 and 12 h, respectively.…”

Effects of Antidepressants on DSP4/CPT-Induced DNA Damage Response in Neuroblastoma SH-SY5Y Cells

“…Antidepressants used were SSRIs (fluoxetine and paroxetine), NRIs (reboxetine), TCAs (imipramine, amitriptyline and DMI) and monoamine oxidase inhibitors (MAOIs, l-deprenyl and pargyline). As mentioned in materials and methods, the selection of these antidepressant concentrations are based on the published papers (Lai & Yu 1997, Koshimura et al 2000, Seymour et al 2003, Taler et al 2007, Hisaoka et al 2008, Fisar et al 2010, Leskiewicz et al 2013, Jantas et al 2014), in which different antidepressants in clinically relevant concentrations exhibited neuronal protection without effects on cell viability when used alone in SH-SY5Y cells or PC12 cells. Based on the provided information, we performed preliminary experiments and selected two concentrations for each antidepressant under the present experimental conditions.…”

“…Therefore, the neuroprotective effects accounted by antidepressants, as demonstrated in the present study, may act via these pathways too. It was reported that the antidepressants tianeptine and moclobemide, both MAOIs, prevented apoptosis caused by toxic agent staurosporine, doxorubicin or FasL in vitro through motivating of the ERK1/2 (Chiou et al 2006, Jantas et al 2014). Likewise, imipramine, amitriptyline, DMI, citalopram, fluoxetine, reboxetine and tianeptine blocked dexamethasone-induced decreases in cell viability and proliferation rate trough activating of ERK1/2 (Leskiewicz et al 2013).…”

“…Likewise, imipramine, amitriptyline, DMI, citalopram, fluoxetine, reboxetine and tianeptine blocked dexamethasone-induced decreases in cell viability and proliferation rate trough activating of ERK1/2 (Leskiewicz et al 2013). These antidepressants also protected glia cells from doxorubicin-induced cell death (Jantas et al 2014). Furthermore, tianeptine’s neuroprotective effects against staurosporine- and doxorubicin-evoked cell death in primary cortical neurons and retinoic acid-differentiated SH-SY5Y cells were found through actuating of MAPK/ERK1/2 and PI3-K/Akt pathways (Jantas et al 2014).…”

“…The concentration of CPT was based on published paper from this department (Serrano et al 2013). The selection of antidepressant concentrations is primarily based on the literature (Lai & Yu 1997, Koshimura et al 2000, Taler et al 2007, Hisaoka et al 2008, Leskiewicz et al 2013, Jantas et al 2014) and our preliminary experiments (see the detail on page 7). Only SH-SY5Y cells prior to passage 15 were used.…”