Department of Molecular Medicine and Translational Science, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
Radiat Res. 2012 Jul;178(1):46-56. doi: 10.1667/rr2731.1. Epub 2012 Jun 12.
We hypothesized that chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, to young adult male rats would prevent/ameliorate fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Eighty 12-14-week-old young adult male Fischer 344 rats received either: (1) sham irradiation, (2) 40 Gy of fractionated whole-brain irradiation delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation plus continuous administration of 15 mg/L of ramipril in the drinking water starting 3 days before irradiation, or (4) fractionated whole-brain irradiation plus ramipril. Cognitive function was assessed using a perirhinal cortex-dependent version of the novel object recognition task 26 weeks after irradiation. Microglial activation was determined in the perirhinal cortex and the dentate gyrus of the hippocampus 28 weeks after irradiation using the ED1 antibody. Neurogenesis was assessed in the granular cell layer and subgranular zones of the dentate gyrus using a doublecortin antibody. Fractionated whole-brain irradiation led to: (1) a significant impairment in perirhinal cortex-dependent cognitive function, (2) a significant increase in activated microglia in the dentate gyrus but not in the perirhinal cortex, and (3) a significant decrease in neurogenesis. Continuous administration of ramipril before, during, and after irradiation prevented the fractionated whole-brain irradiation-induced changes in perirhinal cortex-dependent cognitive function, as well as in microglial activation in the dentate gyrus. Thus, as hypothesized, continuous administration of the angiotensin-converting enzyme inhibitor, ramipril, can prevent the fractionated whole-brain irradiation-induced impairment in perirhinal cortex-dependent cognitive function.
我们假设，对年轻成年雄性大鼠进行血管紧张素转换酶抑制剂雷米普利的慢性给药，将预防/改善分阶段全脑照射引起的边缘皮层依赖性认知障碍。80 只 12-14 周龄的成年雄性 Fischer 344 大鼠接受以下处理之一：（1）假照射，（2）40Gy 分阶段全脑照射，每周 2 次，每次 5Gy，共 4 周，（3）假照射加在照射前 3 天开始连续饮用 15mg/L 雷米普利的饮用水，或（4）分阶段全脑照射加雷米普利。照射后 26 周，使用边缘皮层依赖性新物体识别任务评估认知功能。照射后 28 周，使用 ED1 抗体测定边缘皮层和海马齿状回的小胶质细胞激活情况。使用双皮质素抗体评估齿状回颗粒细胞层和亚颗粒层的神经发生情况。分阶段全脑照射导致：（1）边缘皮层依赖性认知功能显著受损，（2）齿状回中激活的小胶质细胞显著增加，但边缘皮层中无明显增加，（3）神经发生显著减少。在照射前、照射期间和照射后连续给予雷米普利可预防分阶段全脑照射引起的边缘皮层依赖性认知功能变化，以及齿状回中小胶质细胞的激活。因此，正如假设的那样，血管紧张素转换酶抑制剂雷米普利的连续给药可以预防分阶段全脑照射引起的边缘皮层依赖性认知功能障碍。
