Acharya Munjal M, Baulch Janet E, Lusardi Theresa A, Allen Barrett D, Chmielewski Nicole N, Baddour Al Anoud D, Limoli Charles L, Boison Detlev
Department of Radiation Oncology, University of California Irvine, CA, USA.
R. S. Dow Neurobiology Laboratories, Legacy Research Institute Portland, OR, USA.
Front Mol Neurosci. 2016 Jun 3;9:42. doi: 10.3389/fnmol.2016.00042. eCollection 2016.
Clinical radiation therapy for the treatment of CNS cancers leads to unintended and debilitating impairments in cognition. Radiation-induced cognitive dysfunction is long lasting; however, the underlying molecular and cellular mechanisms are still not well established. Since ionizing radiation causes microglial and astroglial activation, we hypothesized that maladaptive changes in astrocyte function might be implicated in radiation-induced cognitive dysfunction. Among other gliotransmitters, astrocytes control the availability of adenosine, an endogenous neuroprotectant and modulator of cognition, via metabolic clearance through adenosine kinase (ADK). Adult rats exposed to cranial irradiation (10 Gy) showed significant declines in performance of hippocampal-dependent cognitive function tasks [novel place recognition, novel object recognition (NOR), and contextual fear conditioning (FC)] 1 month after exposure to ionizing radiation using a clinically relevant regimen. Irradiated rats spent less time exploring a novel place or object. Cranial irradiation also led to reduction in freezing behavior compared to controls in the FC task. Importantly, immunohistochemical analyses of irradiated brains showed significant elevation of ADK immunoreactivity in the hippocampus that was related to astrogliosis and increased expression of glial fibrillary acidic protein (GFAP). Conversely, rats treated with the ADK inhibitor 5-iodotubercidin (5-ITU, 3.1 mg/kg, i.p., for 6 days) prior to cranial irradiation showed significantly improved behavioral performance in all cognitive tasks 1 month post exposure. Treatment with 5-ITU attenuated radiation-induced astrogliosis and elevated ADK immunoreactivity in the hippocampus. These results confirm an astrocyte-mediated mechanism where preservation of extracellular adenosine can exert neuroprotection against radiation-induced pathology. These innovative findings link radiation-induced changes in cognition and CNS functionality to altered purine metabolism and astrogliosis, thereby linking the importance of adenosine homeostasis in the brain to radiation injury.
用于治疗中枢神经系统癌症的临床放射疗法会导致意外且使人衰弱的认知障碍。辐射诱发的认知功能障碍持续时间很长；然而，其潜在的分子和细胞机制仍未完全明确。由于电离辐射会导致小胶质细胞和星形胶质细胞活化，我们推测星形胶质细胞功能的适应性改变可能与辐射诱发的认知功能障碍有关。在其他神经胶质递质中，星形胶质细胞通过腺苷激酶（ADK）的代谢清除作用来控制内源性神经保护剂和认知调节剂腺苷的可用性。成年大鼠接受头颅照射（10 Gy）后，采用临床相关方案，在暴露于电离辐射1个月后，其依赖海马体的认知功能任务[新位置识别、新物体识别（NOR）和情境恐惧条件反射（FC）]的表现显著下降。与对照组相比，接受照射的大鼠探索新位置或新物体的时间减少。在FC任务中，头颅照射还导致与对照组相比，冻结行为减少。重要的是，对接受照射的大脑进行免疫组织化学分析显示，海马体中ADK免疫反应性显著升高，这与星形胶质细胞增生以及胶质纤维酸性蛋白（GFAP）表达增加有关。相反，在头颅照射前用ADK抑制剂5-碘结核菌素（5-ITU，3.1 mg/kg，腹腔注射，共6天）治疗的大鼠，在暴露1个月后的所有认知任务中，行为表现均显著改善。5-ITU治疗减轻了辐射诱发的星形胶质细胞增生，并降低了海马体中ADK免疫反应性。这些结果证实了一种星形胶质细胞介导的机制，即细胞外腺苷的保留可对辐射诱发的病理过程发挥神经保护作用。这些创新性发现将辐射诱发的认知和中枢神经系统功能变化与嘌呤代谢改变和星形胶质细胞增生联系起来，从而将大脑中腺苷稳态的重要性与辐射损伤联系起来。
