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.

项目摘要 /摘要 该提议的长期目标是减少正常中枢神经系统中放射治疗的不良后期作用 组织最终改善生活质量并扩大脑肿瘤患者的存活。放射治疗 经常用于手术切除后原发性或转移性脑肿瘤的患者，或在扩散的患者中 不可易受的脑肿瘤。但是，大脑的放射治疗通常会导致神经认知缺陷 功能，限制了可以安全给予的辐射剂量的水平。因此，有一个 减少正常脑组织放射治疗的晚期作用的迫切需要。认知障碍 指向海马中的持续缺陷。动物模型的研究表明，持续的氧化应激， 中枢神经系统的炎症，树突网络的损耗以及神经营养因素的产生降低可能 通过阻碍网络连接并减少生产来促进学习和记忆的缺陷 海马中的新神经元。基于这些发现，我们使用了基于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，7,8-二氢氟氟酮（7,8-- DHF），模仿小鼠颅辐照研究中神经营养因子的作用。我们发现两种药物 增加对学习和记忆重要的新神经元的产生，但每个神经元都影响了不同的过程 新的神经元产生。 Mnbuoe促进了未成熟神经元的产生，但支持7,8-DHF 新生儿神经元的成熟和长期生存。此外，7,8-DHF治疗也导致了保留 正常的认知功能，树突状脊柱密度和突触蛋白水平。互补行动 在这两种药物中，我们假设我们在此期间与mnbuoe和7,8-DHF合并 放射治疗的不同阶段可能会在保持正常状态下提供添加剂或协同作用 认知功能。检验假设并检查保留认知的基本机制 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 颅辐照后，年轻小鼠的认知功能治疗； （2）检查 颅辐照后，MNBUOE和7,8-DHF治疗中年小鼠的认知功能； （3） 研究MNBUOE和7,8-DHF治疗对中年小鼠抑制性神经元的影响 颅辐照； （4）检查MNBUOE，7,8-DHF和颅辐射的联合处理如何影响 胶质母细胞瘤的生长或存活。非肿瘤轴承小鼠将通过不同的组合处理 Mnbuoe和7,8-DHF颅骨辐照前后。行为，免疫组织化学，生化和 分子生物学方法将用于研究认知功能，树突结构的变化， 神经炎症和突触可塑性。电生理方法将用于检查 海马中的快速峰值白蛋白阳性（PV+）中间神经元，以更好地了解 该神经元种群的辐射。异种移植模型将用于检查mnbuoe和7,8-的影响 颅辐照后DHF关于肿瘤生长和宿主存活。成功完成拟议的 研究将有助于建立一种新的治疗组合，该组合可以有效地降低或逆转不利 颅辐照对神经认知功能的影响，而不必降低辐射的疗效 - 介导的肿瘤抑制。由于保留了认知功能，新的治疗组合可能 通过允许可以安全给予的更高剂量的辐射来提高辐射疗法的功效 用于癌症治疗。