Genotoxic and oxidative effect of duloxetine on mouse brain and liver tissues

Abstract

We evaluated the duloxetine DNA damaging capacity utilizing the comet assay applied to mouse brain and liver cells, as well as its DNA, lipid, protein, and nitric oxide oxidative potential in the same cells. A kinetic time/dose strategy showed the effect of 2, 20, and 200 mg/kg of the drug administered intraperitoneally once in comparison with a control and a methyl methanesulfonate group. Each parameter was evaluated at 3, 9, 15, and 21 h postadministration in five mice per group, except for the DNA oxidation that was examined only at 9 h postadministration. Results showed a significant DNA damage mainly at 9 h postexposure in both organs. In the brain, with 20 and 200 mg/kg we found 50 and 80% increase over the control group (p ≤ 0.05), in the liver, the increase of 2, 20, and 200 mg/kg of duloxetine was 50, 80, and 135% in comparison with the control level (p ≤ 0.05). DNA, lipid, protein and nitric oxide oxidation increase was also observed in both organs. Our data established the DNA damaging capacity of duloxetine even with a dose from the therapeutic range (2 mg/kg), and suggest that this effect can be related with its oxidative potential.

Effects of Duloxetine on Oxidant-Antioxidant System in Rat Brain Tissues

“…For example, in a study using the comet assay on mouse liver and brain cells, duloxetine caused significant DNA damage and increased DNA, lipid, protein and NO oxidation in both organs mainly after 9 hours. Even at a dose of 2 mg/kg, duloxetine has been reported to have the capacity to damage DNA, and it has been suggested that this effect may be due to its oxidative potential (37). In our study, we found a non-significant decrease in rat brain NO levels after duloxetine treatment for 14 days.…”

“…This nonsignificant decrease caused by duloxetine on the NO levels suggested that it would not have a negative effect on the oxidant-antioxidant system at least through NO, which is an inorganic free radical. Perhaps duloxetine may have an oxidative potential by increasing NO oxidation in the acute period in short-term applications (37), however, in longterm treatments such as the one in our study, this oxidative effect it has through NO may be eliminated.…”

“…However, excessive NO synthesis has been found to damage neurons (36). Studies evaluating the effect of duloxetine on NO are available in the literature (37). For example, in a study using the comet assay on mouse liver and brain cells, duloxetine caused significant DNA damage and increased DNA, lipid, protein and NO oxidation in both organs mainly after 9 hours.…”

Genotoxic and cytotoxic evaluation of venlafaxine in an acute and a subchronic assay in mouse

“…Besides, Singh and Sharma (2016) established that rat prenatal exposure to venlafaxine enhances the generation of reactive oxygen species, a situation which played a key role in regulating the release of pro-apoptotic factors from mitochondria, thereby heightening apoptotic neurodegeneration that affects proliferation, migration and differentiation of cells. Also, our geno/cytotoxic results are also in line with the increase of reactive oxygen species found in rat neocortices exposed to the drug (Sinh et.al., 2015), moreover, other antidepressants, such as duloxetine, have produced oxidative damage to lipids, proteins, and DNA in mouse liver and brain (Alvarez-González et al, 2021). However, the conclusion reached on this matter is presently controversial given that venlafaxine has also been reported to have antioxidant potential.…”