Mitigation of cognitive impairments from radiation therapy

项目摘要/摘要 这项建议的长期目标是减少正常中枢神经系统放射治疗的不良后遗症。 最终提高脑肿瘤患者的生活质量和延长生存期。放射疗法 常用于手术切除后的原发性或转移性脑肿瘤患者，或弥漫性脑肿瘤患者。 无法手术的脑瘤。然而，大脑中的放射治疗往往会导致神经认知缺陷。 功能，这限制了可安全使用的辐射剂量水平。因此，有一个 迫切需要减少放射治疗对正常脑组织的后遗症。认知障碍 指向海马体的持续性缺陷。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，树突状细胞网络的磨损，以及神经营养因子的减少可能 通过阻碍网络连接和减少产生 海马区的新神经元。基于这些发现，我们使用了一种基于锰卟啉的氧化还原活性药物， MnBuOE，以抑制氧化应激和小分子黄酮类化合物7，8-二羟基黄酮(7，8-二羟基黄酮) DHF)，以模拟神经营养因子在小鼠颅脑照射研究中的作用。我们发现这两种药物 增加对学习和记忆重要的新神经元的产生，但每个神经元都有不同的作用过程 新神经元的产生。而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。互补的行动 这两种药物中的一种使我们假设在治疗过程中联合使用MnBuOE和7，8-DHF 放射治疗的不同阶段可能会在维持正常状态方面提供相加或协同效应 认知功能。来检验这一假说并检验被保留的认知的机制 从MnBuOE和7，8-DHF的作用来看，我们建议：(1)评估MnBuOE和7，8-DHF的影响 不同治疗方法对幼年小鼠颅脑照射后认知功能的影响 MnBuOE和7，8-DHF对中年小鼠颅脑照射后认知功能的影响 观察MnBuOE和7，8-DHF对中年小鼠脑内抑制性神经元的影响 以及(4)观察联合应用MnBuOE、7，8-DHF和头颅照射的效果。 胶质母细胞瘤的生长或存活。非荷瘤小鼠将接受不同组合的治疗 MnBuOE和7，8-DHF在颅脑照射前后的变化。行为、免疫组织化学、生化和 分子生物学方法将被用来研究认知功能、树突结构、 神经炎症和突触可塑性。将使用电生理学方法来检测 海马区快速发放小白蛋白阳性(PV+)中间神经元以更好地了解 对这个神经元群体的辐射。异种移植模型将被用来研究MnBuOE和7，8-Me的作用。 DHF对颅脑照射后肿瘤生长和宿主存活的影响。圆满完成拟议中的 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良反应 颅脑照射对神经认知功能的影响而不一定降低放射的疗效- 介导性肿瘤抑制。由于保留了认知功能，新的治疗组合可能 通过允许可以安全地进行更高剂量的放射治疗来提高放射治疗的疗效 用于癌症治疗。

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.