Neuronal life or death linked to depression treatment: the interplay between drugs and their stress-related outcomes relate to single or combined drug therapies

Abstract

Depression is a serious medical condition, typically treated by antidepressants. Conventional monotherapy can be effective only in 60–80% of patients, thus modern psychiatry deals with the challenge of new methods development. At the same moment, interactions between antidepressants and the occurrence of potential side effects raise serious concerns, which are even more exacerbated by the lack of relevant data on exact molecular mechanisms. Therefore, the aims of the study were to provide up-to-date information on the relative mechanisms of action of single antidepressants and their combinations. In this study, we evaluated the effect of single and combined antidepressants administration on mouse hippocampal neurons after 48 and 96 h in terms of cellular and biochemical features in vitro. We show for the first time that co-treatment with amitriptyline/imipramine + fluoxetine initiates in cells adaptation mechanisms which allow cells to adjust to stress and finally exerts less toxic events than in cells treated with single antidepressants. Antidepressants treatment induces in neuronal cells oxidative and nitrosative stress, which leads to micronuclei and double-strand DNA brakes formation. At this point, two different mechanistic events are initiated in cells treated with single and combined antidepressants. Single antidepressants (amitriptyline, imipramine or fluoxetine) activate cell cycle arrest resulting in proliferation inhibition. On the other hand, treatment with combined antidepressants (amitriptyline/imipramine + fluoxetine) initiates p16-dependent cell cycle arrest, overexpression of telomere maintenance proteins and finally restoration of proliferation. In conclusion, our findings may pave the way to better understanding of the stress-related effects on neurons associated with mono- and combined therapy with antidepressants.

Cell cycle abnormality is a cellular phenotype in OCD

“…In our study, following in vitro fluoxe2ne treatment with 10µM for 24 hrs, we observed an overall reduc2on in the propor2on of G2/M phase cells but there was no difference on the effects of fluoxe2ne between the cases and control lines. These findings are similar to other studies (Lin et al, 2016;Solek et al, 2019), however, the reason why we could not observe differences in other phases especially G0/G1 might be due to short dura2on of fluoxe2ne exposure. A higher concentra2on for longer dura2on may be needed for these effects to occur (Brei€eld et al, 2016;Brei€eld, Scholl, Steffens, Laje, & S2ngl, 2017;Morag et al, 2010).…”

“…Previous studies have shown fluoxe2ne to cause an arrest in the G0/G1 phase in various cell lines (Hoose et al, 2012;Krishnan et al, 2008;Serafeim et al, 2003) along with reduc2on of cells in the G2/M and S phase (Lin et al, 2016;Solek et al, 2019). Some studies have shown these effects ini2ally at 24 hrs with 10µM dose of fluoxe2ne, which is the reason for considering this dose and 2me for our study.…”

“…In this study, we have inves2gated for cell cycle dysregula2on in the LCLs derived from pa2ents with OCD and differen2al effects of in vitro fluoxe2ne treatment based on clinical treatment response to SRIs. There are several studies which have examined the role of fluoxe2ne on cell growth and cell cycle in cancer and depression (Hoose et al, 2012;Krishnan et al, 2008;Lin et al, 2016;Serafeim et al, 2003;Solek et al, 2019). To the best of our knowledge, this is the first study to inves2gate these effects in OCD.…”

Wnt/β-Catenin Signaling in Neural Stem Cell Homeostasis and Neurological Diseases

“…Depression and anxiety disorders are highly prevalent and disabling diseases that cause cognitive impairment within the patient’s lifetime (Solek and others 2019). Increasing evidence has shown that Wnt/β-catenin signaling is associated with depression disorders through the regulation of neurogenesis (Lie and others 2005; Sani and others 2012; Tayyab and others 2018).…”

Amitriptyline interferes with autophagy-mediated clearance of protein aggregates via inhibiting autophagosome maturation in neuronal cells

“…In vitro neuronal cell culture system, amitriptyline does not cause cytotoxicity up to 20 μM (Fig. 1 ) and IC 50 for cell proliferation is reported to be 35.59 ± 3.48 μM 60 . To evaluate whether amitriptyline accumulation through long-term and/or high-dose use could be associated with the increased risk of neurodegenerative disease, we used relatively high concentrations in this study.…”