In vivo Administration of Atorvastatin Does Not Impair Mitochondrial Function or Cellular Viability in the Prefrontal Cortex of Mice

Atorvastatin is a widely prescribed statin used for its cholesterol-lowering effects; however, it also exerts known pleiotropic effects, including antioxidant and anti-inflammatory properties. Atorvastatin´s impact on mitochondrial function remains controversial, with reports of toxicity in skeletal muscle and liver, while exhibiting beneficial effects on the brain. Atorvastatin has a neuroprotective effect, modulating glutamatergic transmission and reducing oxidative stress. Additionally, we previously showed that atorvastatin treatment in vivo increases mitochondrial capacity in the mouse hippocampus. Nonetheless, the bioenergetic impact of atorvastatin on the prefrontal cortex, a critical region for cognitive function, remains underexplored. This study investigated whether short-term administration of atorvastatin alters mitochondrial respiration and redox status in the prefrontal cortex of adult mice. Male Swiss mice received atorvastatin (10 mg/kg/day) or vehicle orally (p.o., in a voluntary consumption protocol) for 7 days. A behavioral analysis showed that atorvastatin slightly increased spontaneous locomotor activity and does not compromise short- (90 min) and long-term (24 h) memory in the object recognition task. The evaluation of cellular viability, cell membrane integrity, reactive oxygen species (ROS) production, and mitochondrial membrane potential in slices from the prefrontal cortex showed that atorvastatin did not induce oxidative stress, cell damage, or mitochondrial depolarization. High-resolution respirometry (HRR) was used to assess oxygen consumption rates (OCR) in prefrontal cortex homogenates, and we observed no significant alterations in any of the mitochondrial respiratory states: basal, LEAK, phosphorylating, maximal electron transfer system (ETS) capacity, or coupling efficiency. Furthermore, direct analysis of the enzymatic activity of respiratory chain complexes I and II also showed no alterations. These findings indicate that short-term atorvastatin administration is bioenergetically neutral in the murine prefrontal cortex under basal conditions, and does not compromise cognition, mitochondrial function, or cellular viability.