Major Depressive Disorder and Oxidative Stress: In Silico Investigation of Fluoxetine Activity against ROS

Abstract

Major depressive disorder is a psychiatric disease having approximately a 20% lifetime prevalence in adults in the United States (U.S.), as reported by Hasin et al. in JAMA Psichiatry 2018 75, 336–346. Symptoms include low mood, anhedonia, decreased energy, alteration in appetite and weight, irritability, sleep disturbances, and cognitive deficits. Comorbidity is frequent, and patients show decreased social functioning and a high mortality rate. Environmental and genetic factors favor the development of depression, but the mechanisms by which stress negatively impacts on the brain are still not fully understood. Several recent works, mainly published during the last five years, aim at investigating the correlation between treatment with fluoxetine, a non-tricyclic antidepressant drug, and the amelioration of oxidative stress. In this work, the antioxidant activity of fluoxetine was investigated using a computational protocol based on the density functional theory approach. Particularly, the scavenging of five radicals (HO•, HOO•, CH3OO•, CH2=CHOO•, and CH3O•) was considered, focusing on hydrogen atom transfer (HAT) and radical adduct formation (RAF) mechanisms. Thermodynamic as well as kinetic aspects are discussed, and, for completeness, two metabolites of fluoxetine and serotonin, whose extracellular concentration is enhanced by fluoxetine, are included in our analysis. Indeed, fluoxetine may act as a radical scavenger, and exhibits selectivity for HO• and CH3O•, but is inefficient toward peroxyl radicals. In contrast, the radical scavenging efficiency of serotonin, which has been demonstrated in vitro, is significant, and this supports the idea of an indirect antioxidant efficiency of fluoxetine.

Fluoxetine scaffold to design tandem molecular antioxidants and green catalysts

“…The radical scavenging activity via HAT of uoxetine has been recently investigated in silico by some of us. 17 HAT occurs from the non-aromatic sites C7, C14, C15, N16 and C17. We have considered the corresponding sites of selenouoxetine (Scheme 1) and focused on the scavenging of HOc, which is the most reactive and electrophilic oxygen centred radical, of the peroxyl radical HOOc and of CH 2 ]CHOOc, which mimics larger unsaturated peroxyl radicals.…”

“…Although the compound demonstrated an antioxidant role, its direct contribution to ROS scavenging is of a minor entity with respect to that of its metabolites. 16,17 In addition, uoxetine contrasts oxidative stress also by increasing extracellular concentration of serotonin, which is a known strong antioxidant. [17][18][19] This neurotransmitter, together with its N-acetyl metabolite, exerts neuroprotection by modulating oxidative burst mechanism and/or the production of superoxide anion radical.…”

“…16,17 In addition, uoxetine contrasts oxidative stress also by increasing extracellular concentration of serotonin, which is a known strong antioxidant. [17][18][19] This neurotransmitter, together with its N-acetyl metabolite, exerts neuroprotection by modulating oxidative burst mechanism and/or the production of superoxide anion radical. 19 Fluoxetine is also thought to act indirectly on oxidative stress by modulating the expression of enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx).…”

“…Besides the radical scavenging activity via HAT (Hydrogen Atom Transfer) mechanism, recently reported for uoxetine, 17 selenouoxetine and its derivatives have the capacity of reducing hydroperoxides and H 2 O 2 as GPx mimics. [23][24][25] The biological role of selenium is a long-debated issue since its identication in GPx, an enzyme able to protect cells from oxidative stress by inactivating hydroperoxides.…”

“…Redox equilibrium involving differently oxidised selenium species.HAT ðkcal mol À1 Þ in the gas phase (a), in benzene (b), and in water (c) for the scavenging of HOc, HOOc and CH 2 ]CHOOc from non-aromatic sites of selenofluoxetine. Values for fluoxetine taken from Muraro et al17 are showed in a lighter shade for comparison. Level of theory:(SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d).This journal is © The Royal Society of Chemistry 2020 RSC Adv., 2020, 10, 18583-18593 | 18589 Paper RSC Advances Open Access Article.…”