Mitigation of cognitive impairments from radiation therapy

减轻放射治疗造成的认知障碍

• 批准号: 10266067
• 负责人: Ting-Ting Huang
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266067
• 关键词: Adverse effects; Affect; Age; Agonist; Animal Model; Animals; Behavioral; Behavioral Paradigm; Biochemical; Biological; Brain; Brain Injuries; Brain Neoplasms; Cancer Patient; Cell Survival; Combined Modality Therapy; Cranial Irradiation; Defect; Dementia; Dendritic Spines; Diffuse; Electrophysiology (science); Excision; Flavonoids; Future; Generations; Genes; Glioblastoma; Goals; Growth; Healthcare; Hippocampus (Brain); Impaired cognition; Impairment; Individual; Inflammation; Interneurons; Knowledge; Late Effects; Learning; Mediating; Memory; Metastatic malignant neoplasm to brain; Methods; Modality; Modeling; Molecular; Mus; Neurocognitive; Neurocognitive Deficit; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Normal tissue morphology; Operative Surgical Procedures; Oxidation-Reduction; Oxidative Stress; Parvalbumins; Patients; Pharmaceutical Preparations; Population; Porphyrins; Process; Production; Prophylactic treatment; Proteins; Quality of life; Radiation; Radiation Dose Unit; Radiation Protection; Radiation therapy; Structural Protein; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Tumor Suppression; Tumor-infiltrating immune cells; Xenograft Model; age group; base; brain tissue; cancer radiation therapy; cancer therapy; chemobrain; chemotherapy; clinically relevant; cognitive function; cognitive testing; density; efficacious treatment; improved; inhibitory neuron; insight; leukemia; lung small cell carcinoma; malignant breast neoplasm; middle age; military veteran; mouse model; neurogenesis; neuroinflammation; neurotrophic factor; newborn neuron; operation; preservation; prevent; radiation adverse effect; small molecule; stem cells; success; symptom management; tumor; tumor growth; young adult

PROJECT SUMMARY / ABSTRACT The long-term goal of this proposal is to reduce the adverse late effects of radiation therapy in normal CNS tissues to ultimately improve the quality of life and extend survival of patients with brain tumors. Radiation therapy is frequently used in patients with primary or metastatic brain tumors following surgical resection, or in diffused non-operable brain tumors. However, radiation therapy in the brain often leads to defects in neurocognitive functions, which limits the level of radiation doses that can be safely administered. Consequently, there is a critical need to reduce the late effects of radiation therapy in normal brain tissues. The cognitive impairments point to persistent defects in the hippocampus. Studies in animal models suggest that persistent oxidative stress, inflammation in the CNS, attrition of the dendritic networks, and reduced production of neurotrophic factors may contribute to deficits in learning and memory by hindering network connectivity and reducing the production of new neurons in the hippocampus. Based on these findings, we used a Mn porphyrin-based redox-active drug, MnBuOE, to suppress oxidative stress and a small molecule flavonoid compound, 7,8-dihydrxyflavone (7,8- DHF), to mimic the action of neurotrophic factors in cranial irradiation studies with mice. We found both drugs to increase the production of new neurons important for learning and memory, but each effected a different process of new neuron production. Whereas MnBuOE promoted the production of immature neurons, 7,8-DHF supported maturation and long-term survival of newborn neurons. Furthermore, 7,8-DHF treatment also led to preserved normal cognitive functions, dendritic spine densities, and synaptic proteins levels. The complementary actions of these two drugs leads us to hypothesize that combined treatment with MnBuOE and 7,8-DHF during different stages of radiation therapy may provide additive or synergistic effects in preserving normal cognitive functions. To test the hypothesis and examine the mechanisms underlying preserved cognitive functions from MnBuOE and 7,8-DHF treatment, we propose to (1) assess the impacts of MnBuOE and 7,8-DHF treatments on cognitive functions in young adult mice following cranial irradiation; (2) examine the effects of MnBuOE and 7,8-DHF treatments on cognitive functions in middle-aged mice following cranial irradiation; (3) investigate the effects of MnBuOE and 7,8-DHF treatments on inhibitory neurons in middle-aged mice following cranial irradiation; and (4) examine how combined treatments of MnBuOE, 7,8-DHF, and cranial irradiation affect the growth or survival of glioblastoma. Non-tumor bearing mice will be treated with different combinations of MnBuOE and 7,8-DHF before and after cranial irradiation. Behavioral, immunohistochemical, biochemical, and molecular biological approaches will be used to investigate changes in cognitive functions, dendritic structures, neuroinflammation, and synaptic plasticity. Electrophysiology methods will be used to examine the function of fast spiking parvalbumin positive (PV+) interneurons in the hippocampus to better understand the impact of radiation on this neuronal population. A xenograft model will be used to examine the effects of MnBuOE and 7,8- DHF on tumor growth and host survival following cranial irradiation. Successful completion of the proposed studies will help to establish a new treatment combination that can effectively decrease or reverse the adverse effects of cranial irradiation on neurocognitive functions without necessarily reducing the efficacy of radiation- mediated tumor suppression. As a result of preserved cognitive functions, the new treatment combination may increase the efficacy of radiation therapy by allowing higher doses of radiation that can be safely administered for cancer treatment.

项目总结/摘要 这项建议的长期目标是减少放射治疗对正常中枢神经系统的不良迟发效应 最终改善脑肿瘤患者的生活质量并延长其生存期。放射治疗 常用于手术切除后的原发性或转移性脑肿瘤患者， 不可手术的脑瘤然而，脑部的放射治疗往往导致神经认知功能的缺陷， 功能，这限制了可以安全管理的辐射剂量水平。因此，有一个 迫切需要减少放射治疗对正常脑组织的后期影响。认知障碍 表明海马体存在持续性缺陷动物模型研究表明，持续的氧化应激， 中枢神经系统的炎症、树突状网络的磨损和神经营养因子的产生减少可能 通过阻碍网络连接和减少生产， 海马体中的新神经元基于这些发现，我们使用基于Mn卟啉的氧化还原活性药物， MnBuOE，抑制氧化应激和小分子类黄酮化合物，7，8-二羟基黄酮（7，8-dihydroxyflavone， DHF），以模拟神经营养因子在小鼠脑照射研究中的作用。我们发现这两种药物 增加对学习和记忆很重要的新神经元的产生，但每种都影响不同的过程 新神经元的产生。MnBuOE促进未成熟神经元的产生，而7，8-DHF支持 新生神经元的成熟和长期存活。此外，7，8-DHF处理也导致保存 正常认知功能、树突棘密度和突触蛋白水平。补充行动 这两种药物的联合治疗使我们假设， 放射治疗的不同阶段可以在保持正常的 认知功能为了验证这一假设，并研究保留认知功能的机制， 从MnBuOE和7，8-DHF治疗的功能，我们建议（1）评估MnBuOE和7，8-DHF的影响 治疗对年轻成年小鼠脑照射后认知功能的影响;（2）检查 MnBuOE和7，8-DHF治疗对脑照射后中年小鼠认知功能的影响; 研究MnBuOE和7，8-DHF治疗对中年小鼠中抑制性神经元的影响， 颅照射;（4）检查MnBuOE，7，8-DHF和颅照射联合治疗如何影响 胶质母细胞瘤的生长或存活。非荷瘤小鼠将用以下的不同组合治疗： MnBuOE和7，8-DHF。行为学、免疫组织化学、生物化学和 分子生物学方法将用于研究认知功能，树突结构， 神经炎症和突触可塑性。电生理学方法将被用来检查的功能， 快速尖峰小白蛋白阳性（PV+）中间神经元在海马，以更好地了解的影响， 辐射对这些神经元的影响将使用异种移植模型来检查MnBuOE和7，8-二硝基甲苯的作用。 DHF对颅照射后肿瘤生长和宿主存活的影响。圆满完成拟议的 研究将有助于建立一种新的治疗组合，可以有效地减少或逆转不利的 颅脑照射对神经认知功能的影响，但不一定会降低辐射的疗效- 介导的肿瘤抑制。由于保留了认知功能，新的治疗组合可能 通过允许可以安全施用的更高剂量的放射来增加放射治疗的功效 用于癌症治疗。