McGuiness James A, Scheinert Rachel B, Asokan Aditya, Stadler Vivien-Charlott, Lee Christian S, Rani Asha, Kumar Ashok, Foster Thomas C, Ormerod Brandi K
Department of Neuroscience, University of FloridaGainesville, FL, United States.
McKnight Brain Institute, University of FloridaGainesville, FL, United States.
Front Aging Neurosci. 2017 Sep 5;9:280. doi: 10.3389/fnagi.2017.00280. eCollection 2017.
We tested whether indomethacin or rosiglitazone treatment could rejuvenate spatial ability and hippocampal neurogenesis in aging rats. Young (4 mo; = 30), middle-aged (12 mo; = 31), and aged (18 mo; = 31) male Fischer 344 rats were trained and then tested in a rapid acquisition water maze task and then fed vehicle (500 μl strawberry milk), indomethacin (2.0 mg/ml), or rosiglitazone (8.0 mg/ml) twice daily for the remainder of the experiment. A week after drug treatment commenced, the rats were given 3 daily BrdU (50 mg/kg) injections to test whether age-related declines in neurogenesis were reversed. One week after the final BrdU injection (~2.5 weeks after the 1st water maze session), the rats were trained to a find novel hidden water maze platform location, tested on 15 min and 24 h probe trials and then killed 24 h later. During the first water maze session, young rats outperformed aged rats but all rats learned information about the hidden platform location. Middle-aged and aged rats exhibited better memory probe trial performances than young rats in the 2nd water maze session and indomethacin improved memory probe trial performances on the 2nd vs. 1st water maze session in middle-aged rats. Middle-aged rats with more new neurons had fewer phagocytic microglia and exhibited better hidden platform training trial performances on the 2nd water maze session. Regardless of age, indomethacin increased new hippocampal neuron numbers and both rosiglitazone and indomethacin increased subependymal neuroblasts/neuron densities. Taken together, our results suggest the feasibility of studying the effects of longer-term immunomodulation on age-related declines in cognition and neurogenesis.
我们测试了吲哚美辛或罗格列酮治疗是否能恢复衰老大鼠的空间能力和海马神经发生。将年轻（4个月；n = 30）、中年（12个月；n = 31）和老年（18个月；n = 31）雄性Fischer 344大鼠进行训练，然后在快速获取水迷宫任务中进行测试，随后在实验剩余时间内每天两次喂食溶剂（500 μl草莓牛奶）、吲哚美辛（2.0 mg/ml）或罗格列酮（8.0 mg/ml）。药物治疗开始一周后，给大鼠每日注射3次溴脱氧尿苷（BrdU，50 mg/kg），以测试与年龄相关的神经发生下降是否得到逆转。在最后一次BrdU注射一周后（第一次水迷宫实验后约2.5周），训练大鼠寻找新的隐藏水迷宫平台位置，在15分钟和24小时的探索实验中进行测试，然后在24小时后处死。在第一次水迷宫实验中，年轻大鼠的表现优于老年大鼠，但所有大鼠都学习到了关于隐藏平台位置的信息。在第二次水迷宫实验中，中年和老年大鼠在记忆探索实验中的表现优于年轻大鼠，并且吲哚美辛改善了中年大鼠在第二次与第一次水迷宫实验中的记忆探索实验表现。新神经元较多的中年大鼠吞噬性小胶质细胞较少，并且在第二次水迷宫实验的隐藏平台训练实验中表现更好。无论年龄如何，吲哚美辛增加了海马新神经元数量，罗格列酮和吲哚美辛都增加了室管膜下神经母细胞/神经元密度。综上所述，我们的结果表明研究长期免疫调节对与年龄相关的认知和神经发生下降的影响是可行的。
