Melatonin Prevents Thymic Atrophy but Does Not Protect Against Disruption of T Cell Maturation Related to Cyclophosphamide Exposure

Increased oxidative stress and apoptosis are key mechanisms of thymic atrophy induced by cyclophosphamide (CYP). Atrophy leads to changes in the thymic microenvironment and disrupts T cell maturation. The hormone melatonin displays antioxidant and antiapoptotic effects. Here, we tested the hypothesis that melatonin would act as a cytoprotective agent against the harmful effects of CYP in the thymus. A single dose of CYP (300 mg/kg; ip) was injected in male C57BL/6 mice pretreated or not with melatonin (10 mg/kg/day, ip) for 4 days. Atrophy, oxidative stress and apoptosis markers, and T cell subpopulations were evaluated in the thymus 24 h after CYP injection. Melatonin partially prevented atrophy and the increase in caspase 3 activity induced by CYP. Augmented lipoperoxidation and generation of NADPH-oxidase derived superoxide (O₂^•−), as well as decreased superoxide dismutase (SOD) activity, were detected in the thymus of CYP-injected mice. Pretreatment with melatonin abrogated these responses. CYP reduced the number of double-positive (CD4⁺CD8⁺) cells, activated single-positive (CD8⁺ and CD4⁺) cells, and regulatory CD4⁺FoxP3⁺ (Treg) cells in the thymus. None of these effects were reversed by melatonin. In conclusion, melatonin partially prevented thymic atrophy, possibly by reducing apoptosis and oxidative stress. However, melatonin did not abrogate the immunomodulatory effect of CYP on T cell populations. The lack of effect of melatonin on CYP-induced reduction in Treg cells may be of interest since these cells reduce antitumor immunity.