Atomoxetine produces oxidative stress and alters mitochondrial function in human neuron-like cells

Abstract

Atomoxetine (ATX) is a non-stimulant drug used in the treatment of attention-deficit/hyperactivity disorder (ADHD) and is a selective norepinephrine reuptake inhibitor. It has been shown that ATX has additional effects beyond the inhibition of norepinephrine reuptake, affecting several signal transduction pathways and alters gene expression. Here, we study alterations in oxidative stress and mitochondrial function in human differentiated SH-SY5Y cells exposed over a range of concentrations of ATX. We found that the highest concentrations of ATX in neuron-like cells, caused cell death and an increase in cytosolic and mitochondrial reactive oxygen species, and alterations in mitochondrial mass, membrane potential and autophagy. Interestingly, the dose of 10 μM ATX increased mitochondrial mass and decreased autophagy, despite the induction of cytosolic and mitochondrial reactive oxygen species. Thus, ATX has a dual effect depending on the dose used, indicating that ATX produces additional active therapeutic effects on oxidative stress and on mitochondrial function beyond the inhibition of norepinephrine reuptake.

Evaluation of the efficacy of drug treatment based on measurement of the oxidative stress, using reactive oxygen metabolites and biological antioxidant potential, in children with autism spectrum disorder and attention deficit hyperactivity disorder

“…Atomoxetine hydrochloride, which was prescribed for 18.0% of the study subjects, has been reported to cause mitochondrial dysfunction when used at high concentrations [25]. Therefore, it is considered highly necessary to assess oxidative stress using objective biomarkers for selecting the appropriate drug dose.…”

Role of Oxidative Stress and Neuroinflammation in Attention-Deficit/Hyperactivity Disorder

“…In that sense, it was demonstrated that ATX treatment increases extracellular catecholamine levels [ 22 , 72 ]. Therefore, ATX can trigger an increase of cytosolic and mitochondrial ROS, producing damage to the mitochondria and consequently, cell death [ 80 ]. The precise association between the auto-oxidation of catecholamines and the generation of oxidative stress in ADHD remains unclear.…”

Antioxidants as a Potential Target against Inflammation and Oxidative Stress in Attention-Deficit/Hyperactivity Disorder

“…On the other hand, it has been shown that dopamine and norepinephrine can easily undergo auto-oxidation, forming ROS [125,126], which could lead to cell damage and damage to DNA [127,128]. Also, it has been shown that ATX treatment increases extracellular norepinephrine and dopamine levels [19,129], which would produce an increase in oxidative stress and, as a consequence, cell damage and mitochondrial dysfunction [130]. The brain is particularly susceptible to oxidative stress because of its high lipid content and the high demand for energy consumption [131].…”