Mitigation of Brain Inflammation and Cognitive Impairment after Radiation Injury

神经认知障碍显然与放射治疗有关，特别是在儿童中，当他们 是救生程序的主要有害副作用。大脑功能的长期变化 在辐射事故环境中暴露于辐射的个人中也有描述(例如 切尔诺贝利)。虽然不像致命性和致命性的典型综合症那样戏剧性或危及生命 亚致死剂量的辐射暴露，辐射诱导的认知能力的改变可能会出现显著的 对于在辐射事故或核灾难中幸存下来的个人来说，这是终身的负担。积累 有证据表明，脑辐射损伤会导致大脑环境中持续的变化，表现在 作为内源性神经胶质细胞激活、外周免疫招募的动物模型 细胞因子、趋化因子以及活性氧和氮物种的慢性升高。我们 假设这种神经炎性环境导致神经认知缺陷，包括抑制 海马神经发生和突触功能。因此，拟议研究的一个主要目标是 确定使用抑制神经纤维生成和/或产生ROS的药物是否会导致中毒 辐射诱导的炎性细胞数量、细胞因子的表达、ROS的产生 海马区神经发生和神经认知效应。我们将在成年小鼠身上探索这一假设 两种暴露条件(外部和内部辐射)和在新生动物中，我们预计 效果有待加强。我们还将确定暴露在辐射中的动物是否准备好接受更大的 用脂多糖挑战后出现神经认知障碍，脂多糖是一种已知的改变学习和 记忆。最后，我们将探讨全身照射与热烧伤相结合的可能性。 会加剧中枢神经系统的影响。该项目的具体成果将包括开发4个 研究脑辐射损伤和认知缺陷之间关系的小鼠模型 作为三种药物的试验，每种药物都通过不同的机制来降低神经炎性状态 并有可能恢复认知能力。

Neurocognitive deficits are cleariy associated with radiation therapy, particulariy in children where they represent a major detrimental side effect of life-saving procedures. Long-standing changes in brain function have also been described in individuals exposed to radiafion in the setting of radiological accidents (e.g Chernobyl). Although not as dramatic or life threatening as the classic syndromes associated with lethal and sub-lethal radiafion exposure, radiafion-induced changes in cognitive capacity will likely present a significant and life-long burden to individuals surviving a radiological accident or nuclear disaster. Accumulating evidence suggests that brain radiafion injury leads to a persistent alterafion in the brain's milieu, manifest in animal models over many months as acfivafion of endogenous glial cells, recruitment of peripheral immune cells, and chronic elevation of cytokines, chemokines, and reactive oxygen and nitrogen species. We hypothesize that this neuroinflammatory milieu contributes to neurocognifive deficits, including inhibifion of hippocampal neurogenesis and synapfic function. Therefore, a major goal of the proposed studies is to determine whether use of agents that inhibit neuroinfiammafion and/or producfion of ROS can mifigate radiation-induced changes in infiammatory cell populafions, expression of cytokines, producfion of ROS, hippocampal neurogenesis, and neurocognitive effects. We will explore this hypothesis in adult mice under two exposure condifions (external and internal radiafion) and in newly born animals where we expect the effects to be enhanced. We will also determine whether radiafion exposed animals are primed for greater neurocognitive deficits following challenge with lipopolysaccharide, a "second hit" known to alter learning and memory. Finally, we will explore the possibility that total body irradiation combined with thermal burn exacerbates central nervous system effects. Specific outcomes of this project will include development of 4 mouse models for investigafing the relafionship between brain radiation injury and cognitive deficits, as well as tesfing of three drugs, each acfing through a different mechanism to reduce the neuroinflammatory state and potentially restore cognitive capacity.