Abstract
With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways.
Highlights
Cognitive impairment is commonly reported in patients with cancer treated with chemotherapy [1,2]
We have found alterations in protein arginine methyltransferase 1 (PRMT1) expression in a previous study, and growing evidence suggests that PRMT1 plays an essential role in post-translational modification through interaction with myelination-related transcriptomes, which implies that an epigenetic mechanism underlies MTX neurotoxicity
Melatonin did not restore the brain-derived neurotrophic factor (BDNF) exon IV mRNA levels, whereas recovery effects were noted in myelin basic protein (MBP) and Sry-related HMg-box (SOX) mRNA expressions
Summary
Cognitive impairment is commonly reported in patients with cancer treated with chemotherapy [1,2]. Follow-up studies on childhood leukemia survivors revealed impaired intellectual and cognitive functions [6,7,8], which raised interest in the study of the neurologic impact of chemotherapy medications on pediatric cancer survivors. Clinical studies have shown that MTX chemotherapy is responsible for both functional and morphological changes in the brain, and it can result in serious late neurologic sequelae, notably cognitive impairment [10,11,12]. For better understanding of the underlying mechanism interplay between brain neurotrophin and myelination-related transcriptomes and brain functional impairment, we focus on the myelination process change in response to MTX treatment in this study
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