Pathophysiology of Chemotherapy-Induced Cognitive Deficits in Juvenile Rats

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DESCRIPTION (provided by applicant): Although cure rates for children with leukemia are increasing, treatment frequently induces permanent deficits in cognitive function, detectable among survivors. The anticancer drug methotrexate (MTX), which has been central to curative leukemia therapy for six decades, is thought to bear responsibility for much of the observed neurotoxic effects. However the pathophysiology underlying MTX-induced cognitive dysfunction is incompletely understood. Furthermore, there are no proven interventions to protect children with leukemia against developing treatment-induced cognitive deficits. Our innovative research approach will address this significant problem, with the long-term objective of improving quality of life for survivors of childhood leukemia. We have developed an animal model in which clinically relevant doses of MTX are repeatedly administered to juvenile rats, modeling the effects of antileukemic treatment regimens given to young children during a period of continued brain development. Supported by preliminary experiments, we hypothesize that three biochemical consequences of MTX exposure contribute to methotrexate-induced cognitive dysfunction, all triggered by an increase in homocysteine: (1) an increase in homocysteine metabolites, which are excitotoxic agonists at hippocampal glutamate receptors; (2) an increase in homocysteine-mediated oxidative damage to neuronal tissue, and (3) a decrease in folate-dependent methylation leading to demyelinating injury. We and others have observed these biochemical changes after MTX exposure, but it is possible that these changes are simply markers of folate antagonism by methotrexate, and do not directly contribute to MTX-induced cognitive dysfunction. We propose to test these three non-mutually exclusive hypotheses, by sequentially testing the contribution of each one to MTX-induced cognitive deficits, corresponding to our three Specific Aims. In each Aim, we will further characterize the changes in relevant biomarkers, histology, and/or imaging studies specifically among juvenile rats repeatedly exposed to systemic and intrathecal MTX. We will then ask whether pharmacologic interference with the pathway in question will prevent cognitive deficits among juvenile rats treated with MTX. Demonstration of such a preventive effect would prove a significant contribution by that targeted process to MTX-induced cognitive dysfunction. More importantly, such a result would point toward a therapeutic intervention that might protect children treated with MTX for leukemia, bringing us closer to our objective of reducing treatment-related toxicity for children with cancer.