Voluntary Exercise Modulates Cuprizone-Induced Hepatic and Cardiac Toxicity in Mice

Cuprizone (CPZ) is a copper-chelating compound widely used as a toxicological agent that induces mitochondrial dysfunction, oxidative stress, and inflammatory responses. However, the systemic effects of CPZ and the potential modulatory role of exercise on peripheral organ injury remain insufficiently characterized. To evaluate the effects of voluntary exercise on oxidative stress and inflammatory responses in the liver and heart in a cuprizone (CPZ)-induced peripheric toxicity. Male C57BL/6J mice were divided into four groups ( n = 10 per group): Control (CON), Exercise (EX), CPZ, and CPZ + EX. The CON group received carboxymethylcellulose calcium (CMC-Ca) by gavage for six weeks. The CPZ group was given 300 mg/kg/day cuprizone in CMC-Ca. The EX group performed voluntary running-wheel exercise with free access throughout the experimental period, and the CPZ + EX group received both CPZ and exercise. CPZ administration increased hepatic malondialdehyde (MDA), myeloperoxidase (MPO) activity, tumor necrosis factor-α (TNF-α), and interleukin-1 beta (IL-1β) levels while decreasing total antioxidant capacity (TAC) and interleukin-10 (IL-10). Plasma alanine aminotransferase (ALT), aspartate transaminase (AST), and MDA were elevated. Voluntary exercise attenuated these changes by reducing lipid peroxidation and pro-inflammatory markers and by enhancing antioxidant capacity. In the heart, CPZ increased MDA, IL-1β, and MPO, whereas exercise reduced these elevations. No significant differences were observed in cardiac TAC or plasma troponin I levels. CPZ induced oxidative stress and inflammatory responses in the liver and heart, indicating systemic toxicity. Voluntary exercise was associated with modulation of these biochemical and inflammatory alterations, suggesting a potential role in attenuating CPZ-induced peripheral organ stress. Schematic overview of the experimental design and the attenuating effects of voluntary exercise on CPZ-induced oxidative stress and inflammatory alterations in the liver and heart.