Pathophysiology of Chemotherapy-Induced Cognitive Deficits in Juvenile Rats

幼年大鼠化疗引起的认知缺陷的病理生理学

• 批准号: 9122809
• 负责人: PETER D. COLE
• 金额: $ 26.29万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122809
• 关键词: Acute Lymphocytic Leukemia; Address; Adolescent; Adult; Adverse effects; Affect; Agonist; Animal Model; Animals; Antineoplastic Agents; Attention; Biochemical; Biological Markers; Brain; Cerebrum; Child; Childhood Leukemia; Clinical Trials; Cognitive deficits; Development; Diffusion Magnetic Resonance Imaging; Distress; Dose; Folic Acid; Functional disorder; Glutamate Receptor; Glutamates; Goals; Health; Hippocampus (Brain); Histology; Homocysteine; Homocystine; Image; Impaired cognition; Incidence; Interruption; Intervention; Malignant Childhood Neoplasm; Measures; Mediating; Memantine; Membrane; Memory; Memory impairment; Methotrexate; Methylation; Modeling; Myelin Basic Proteins; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuraxis; Neurons; Oxidative Stress; Pathway interactions; Patients; Performance at work; Phase; Preventive; Process; Quality of life; Rattus; Recurrence; Research; Schools; Supplementation; Survivors; Testing; Therapeutic Intervention; Tissues; Toxic effect; Treatment Protocols; Ursidae Family; Visual; Work; analog; antioxidant therapy; cancer therapy; chemotherapy; clinically relevant; clinically significant; cognitive function; defined contribution; effective intervention; improved; innovation; juvenile animal; leukemia; myelination; neurotoxic; neurotoxicity; oxidative damage; pre-clinical; prevent; processing speed; research study; spatial memory; white matter

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

描述（由申请人提供）：尽管白血病儿童的治愈率正在增加，但治疗经常会导致认知功能永久性缺陷，这在幸存者中是可以检测到的。抗癌药物甲氨蝶呤 (MTX) 六十年来一直是白血病治疗的核心药物，被认为是造成大部分观察到的神经毒性作用的原因。然而，MTX 引起的认知功能障碍的病理生理学尚不完全清楚。此外，尚无经过证实的干预措施可以保护白血病儿童免遭治疗引起的认知缺陷。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，其中临床相关剂量的 MTX 被重复给予幼年大鼠，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 暴露的三种生化后果会导致甲氨蝶呤诱导的认知功能障碍，所有这些后果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，它们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神经元组织氧化损伤增加，(3) 髓磷脂碱性蛋白的叶酸依赖性甲基化减少。我们和其他人观察到 MTX 暴露后的这些生化变化，但这些变化可能只是甲氨蝶呤拮抗叶酸的标志，并不直接导致 MTX 诱导的认知功能障碍。我们建议通过依次测试每一种假设对 MTX 引起的认知缺陷的贡献来测试这三种非互斥的假设，这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/或成像研究的变化，特别是反复暴露于全身和鞘内 MTX 的幼年大鼠。然后我们将询问对相关途径的药理干扰是否会预防接受 MTX 治疗的幼年大鼠的认知缺陷。这种预防作用的证明将证明该靶向过程对 MTX 引起的认知功能障碍有重大贡献。更重要的是，这样的结果将表明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