Radiation-induced brain injury and cognitive dysfunction in aging rats

描述（由申请人提供）：全脑照射（WBI）是脑肿瘤和转移瘤的有效治疗方法，但50%或更多接受全脑照射治疗的长期幸存者由于辐射引起的正常脑组织损伤而出现认知缺陷。这些缺陷背后的细胞和分子机制尚不清楚，但很清楚的是，辐射杀死增殖细胞，并诱导急性和慢性氧化应激和炎症反应，从而改变存活细胞的功能。尽管对动物模型中辐射致脑损伤机制的研究已经开始揭示关键途径和介质，但由于成年啮齿动物辐射致脑损伤的实验研究几乎无一例外地使用了非常年轻的成年人，因此将从这些研究中获得的知识转化为临床是困难的。相比之下，在临床人群中，大多数接受WBI治疗的成年患者年龄在50岁或以上。由于大脑衰老伴随着增殖细胞数量的变化以及炎症和氧化应激基础水平的变化，因此WBI对老年人大脑的影响可能与对年轻人的影响有很大不同。我们的初步研究和流行病学证据支持这一预期，即衰老增加了辐射引起的认知能力下降的可能性和严重程度。如果能更好地了解脑外伤后的细胞和分子反应，辐射诱导的认知功能障碍的治疗将大有裨益，但在临床相关的脑外伤治疗方案和相关临床人群的最佳模型动物中，测试辐射诱导的神经生物学测量和认知功能变化是至关重要的。这里提出的实验将i)提供衰老对辐射引起的一系列认知功能缺陷影响的第一个直接测试，ii)阐明导致这些功能变化的关键细胞和分子事件，iii)测试是否使用过氧化物酶体增殖激活受体（PPAR）治疗？激动剂吡格列酮，一种抗炎剂，可预防老年大鼠辐射引起的认知功能障碍。通过对幼龄和老年大鼠辐射损伤的定量分析所提供的信息，对于开发预防或改善辐射诱导的认知功能障碍的治疗方法至关重要。在缺乏这类研究的情况下，一个人面临着靶向损伤机制的重大风险，而这在主要临床人群中可能意义较小。公共卫生相关性：本研究与公共卫生相关，因为它将在一种适合实验操作的动物模型中测试临床相关放射治疗对脑损伤和认知缺陷发展的影响，该模型适当地反映了主要临床人群，中年和老年人。这些研究将促进新的和更有效的治疗方法的发展，以防止或减少辐射引起的脑损伤，从而为癌症患者提供益处。

DESCRIPTION (provided by applicant): Whole brain irradiation (WBI) is an effective treatment for brain tumors and metastases but 50% or more of the long-term survivors treated with WBI suffer cognitive deficits attributed to radiation-induced injury to normal brain tissue. The cellular and molecular mechanisms underlying the deficits are not well understood, but it is clear that radiation kills proliferating cells and also induces acute and chronic oxidative stress and inflammatory responses that alter the function of surviving cells. Although investigations of the mechanisms of radiation-induced brain injury in animal models have begun to reveal key pathways and mediators, translating the knowledge gained from these studies to the clinic is difficult since experimental studies of radiation-induced brain injury in adult rodents have used, almost without exception, very young adults. In contrast, in the clinical population, the majority of adult patients treated with WBI are 50 years of age or older. Since brain aging is accompanied by changes both in proliferating cell populations and in basal levels of inflammation and oxidative stress, the effects of WBI on the older brain are likely to be substantially different from the effects in young adults. This expectation is supported by our preliminary studies and by epidemiological evidence that aging increases the likelihood and the severity of radiation-induced cognitive decline. Treatment of radiation-induced cognitive dysfunction would benefit tremendously from a better understanding of the cellular and molecular responses that follow WBI, but it is critical to test radiation-induced changes in neurobiological measures and cognitive functions following a clinically relevant regimen of WBI and in animals that best model the relevant clinical population. The experiments proposed here will i) provide the first direct test of the effects of aging on radiation-induced deficits in a range of cognitive functions, ii) clarify the key cellular and molecular events that contribute to those functional changes, and iii) test whether treatment with the peroxisomal proliferator-activated receptor (PPAR)? agonist, pioglitazone, an anti-inflammatory agent, prevents radiation-induced cognitive dysfunction in old rats. The information that will be provided by this quantitative analysis of radiation-induced injury in young and old rats is critical to translational efforts to develop therapies to prevent or ameliorate radiation-induced cognitive dysfunction. In the absence of such studies, one runs the significant risk of targeting mechanisms of injury that may be of lesser significance in the primary clinical population. PUBLIC HEALTH RELEVANCE: This research is relative to public health because it will test the effects of a clinically relevant radiation treatment on the development of brain injury and cognitive deficits in an animal model that is amenable to experimental manipulation and that appropriately reflects the primary clinical population, middle age and older adults. Such studies will facilitate the development of new and more efficacious treatments to prevent or reduce radiation-induced brain injury and thereby provide benefits to cancer patients.