Aripiprazole, but Not Olanzapine, Alters the Response to Oxidative Stress in Fao Cells by Reducing the Activation of Mitogen-Activated Protein Kinases (MAPKs) and Promoting Cell Survival.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Olanzapine*/pharmacology ; Oxidative Stress*/drug effects ; Aripiprazole*/pharmacology ; Cell Survival*/drug effects ; Hydrogen Peroxide*/pharmacology ; Hydrogen Peroxide*/metabolism ; Apoptosis*/drug effects; Animals ; Mitogen-Activated Protein Kinases/metabolism ; Cell Line, Tumor ; Mitochondria/metabolism ; Mitochondria/drug effects ; Rats ; Antipsychotic Agents/pharmacology ; Humans ; STAT3 Transcription Factor/metabolism

Prolonged use of atypical antipsychotics (AAPs) is commonly associated with increased cardiovascular disease risk. While weight gain and related health issues are generally considered the primary contributors to this risk, direct interference with mitochondrial bioenergetics, particularly in the liver where these drugs are metabolized, is emerging as an additional contributing factor. Here, we compared the effects of two AAPs with disparate metabolic profiles on the response of Fao hepatoma cells to oxidative stress: olanzapine (OLA), which is obesogenic, and aripiprazole (ARI), which is not. Results showed that cells treated with ARI exhibited resistance to H 2 O 2 -induced oxidative stress, while OLA treatment had the opposite effect. Despite enhanced survival, ARI-treated cells exhibited higher apoptotic rates than OLA-treated cells when exposed to H 2 O 2 . Gene expression analysis of pro- and anti-apoptotic factors revealed that ARI-treated cells had a generally blunted response to H 2 O 2 , contrasting with a heightened response in OLA-treated cells. This was further supported by the reduced activation of MAPKs and STAT3 in ARI-treated cells in response to H 2 O 2 , whereas OLA pre-treatment enhanced their activation. The loss of stress response in ARI-treated cells was consistent with the observed increase in the mitochondrial production of O 2 ^•- , a known desensitizing factor. The physiological relevance of O 2 ^•- in ARI-treated cells was demonstrated by the increase in mitophagy flux, likely related to mitochondrial damage. Notably, OLA treatment protected proteasome activity in Fao cells exposed to H 2 O 2 , possibly due to the better preservation of stress signaling and mitochondrial function. In conclusion, this study highlights the underlying changes in cell physiology and mitochondrial function by AAPs. ARI de-sensitizes Fao cells to stress signaling, while OLA has the opposite effect. These findings contribute to our understanding of the metabolic risks associated with prolonged AAP use and may inform future therapeutic strategies.

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P3-0019 Javna Agencija za Raziskovalno Dejavnost RS; 721236 Treatment E2020-MSCA-ITN; PID2021-122765OB-I00 Agencia Estatal de Investigación

Keywords: MAPK; atypical antipsychotics (AAPs); liver; mitochondria; oxidative stress (OS); schizophrenia; secondary drug effects

N7U69T4SZR (Olanzapine)
82VFR53I78 (Aripiprazole)
BBX060AN9V (Hydrogen Peroxide)
EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
0 (Antipsychotic Agents)
0 (STAT3 Transcription Factor)

Date Created: 20241026 Date Completed: 20241026 Latest Revision: 20241105

20250114

PMC11508229

10.3390/ijms252011119

39456900