Pathophysiology of Chemotherapy-Induced Cognitive Deficits in Juvenile Rats

描述（由申请人提供）：虽然白血病儿童的治愈率正在增加，但治疗经常会导致认知功能的永久性缺陷，在幸存者中可检测到。抗癌药物甲氨蝶呤（MTX），这已经是中央治疗白血病六十年，被认为是承担责任的大部分观察到的神经毒性作用。然而，MTX诱导的认知功能障碍的病理生理机制尚未完全了解。此外，没有经过证实的干预措施可以保护白血病儿童免受治疗引起的认知缺陷的影响。我们的创新研究方法将解决这一重大问题，长期目标是提高儿童白血病幸存者的生活质量。我们已经开发了一种动物模型，其中临床相关剂量的MTX反复给药的幼年大鼠，建模的影响，抗白血病治疗方案给予年幼的儿童在一段时间内继续大脑发育。在初步实验的支持下，我们假设MTX暴露的三个生化后果导致了甲氨蝶呤诱导的认知功能障碍，所有这些都是由同型半胱氨酸的增加引发的：（1）同型半胱氨酸代谢物的增加，这是海马谷氨酸受体的兴奋毒性激动剂;（2）高半胱氨酸介导的对神经元组织的氧化损伤的增加，和（3）导致脱髓鞘损伤的叶酸依赖性甲基化的减少。我们和其他人已经观察到MTX暴露后的这些生化变化，但这些变化可能只是甲氨蝶呤对叶酸拮抗作用的标志物，并不直接导致MTX诱导的认知功能障碍。我们建议测试这三个不相互排斥的假设，依次测试每一个MTX诱导的认知缺陷，对应于我们的三个特定目标的贡献。在每个目标中，我们将进一步表征相关生物标志物、组织学和/或成像研究的变化，特别是在反复暴露于全身和鞘内MTX的幼龄大鼠中。然后，我们将询问是否药理学干预途径的问题，将防止认知功能障碍与MTX治疗的幼年大鼠。这种预防作用的证明将证明该靶向过程对MTX诱导的认知功能障碍的显著贡献。更重要的是，这样的结果将指向一种治疗干预，可以保护接受MTX治疗的白血病儿童，使我们更接近减少癌症儿童治疗相关毒性的目标。

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.