Chemotherapy, while remaining a life-saving treatment, has been associated with many serious neurotoxic side effects collectively known as chemotherapy-related cognitive impairments (CRCI). CRCI affects many cancer survivors and for up to 20 years after treatment completion, affecting several domains of brain function (cognitive, affective, and motoric). Children are particularly vulnerable to chemotherapy and have been impacted in their educational achievements, employment, and even life expectancy. Most common childhood cancers are often treated with folate-inhibitor methotrexate (MTX). Our study aimed at establishing a tumor-free mouse model of MTX-induced long-term brain impairments. We hypothesized that early exposure to MTX would induce an accelerated aging phenotype in brain function. Accordingly, male and female C57BL6/J pups (postnatal day 15) received intraperitoneal injections of saline or MTX (2 mg/kg) once a day for 3 days. Pups were weaned on postnatal day 21 and subsets were behaviorally tested at 8-month-old for motor, affective and cognitive functions. Behavioral outcomes support MTX-induced impairment of spatial learning in both 8-month-old males and females. Furthermore, MTX may induce oxidative damage, early senescence, and cytokine dysregulation, undermining brain functions. Future studies of these markers in different brain regions will provide mechanistic insights into these long-term changes and be used for therapeutic development.
