Pathophysiology of Chemotherapy-Induced Cognitive Deficits in Juvenile Rats

描述(由申请人提供)：尽管白血病儿童的治愈率正在增加，但治疗经常会导致永久性的认知功能障碍，在幸存者中可以检测到。抗癌药物甲氨蝶呤(MTX)60年来一直是治疗白血病的核心药物，被认为对观察到的大部分神经毒性作用负有责任。然而，MTX导致认知功能障碍的病理生理学机制尚不完全清楚。此外，还没有得到证实的干预措施来保护白血病儿童免受治疗引起的认知障碍的影响。我们的创新研究方法将解决这一重大问题，长期目标是改善儿童白血病幸存者的生活质量。我们开发了一种动物模型，在该模型中，临床上相关剂量的MTX重复给予幼年大鼠，以密切模拟在大脑持续发育期间给予幼年儿童的抗白血病治疗方案的效果。在初步实验的支持下，我们假设MTX暴露的三个生化后果与甲氨蝶呤诱导的认知功能障碍有关，均由同型半胱氨酸增加触发：(1)同型半胱氨酸代谢物增加，这是海马谷氨酸受体的兴奋性毒性激动剂；(2)同型半胱氨酸介导的对神经元组织的氧化损伤增加，以及(3)叶酸依赖的髓鞘碱性蛋白甲基化减少。我们和其他人在接触MTX后观察到了这些生化变化，但这些变化可能只是甲氨蝶呤拮抗叶酸的标志，并不直接导致MTX引起的认知功能障碍。我们建议检验这三个非互斥假说，通过顺序测试每一个假说对MTX引起的认知缺陷的贡献，与我们的三个具体目标相对应。在每个目标中，我们将进一步描述相关生物标志物、组织学和/或影像研究的变化，特别是在反复暴露于全身和鞘内MTX的幼年大鼠中。然后，我们将询问对上述途径的药物干预是否可以防止接受MTX治疗的幼年大鼠的认知障碍。这种预防效果的证明将被证明是该靶向过程对MTX引起的认知功能障碍的重大贡献。更重要的是，这样的结果将指向一种治疗干预措施，可能会保护接受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, in order to closely model 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 of myelin basic protein. 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