Central Research Laboratory, Zenyaku Kogyo Co, Ltd, Tokyo, Japan.
J Pharmacol Sci. 2012;119(2):160-6. doi: 10.1254/jphs.12036fp.
The senescence accelerated prone mouse strain 8 (SAMP8) develops age-related deficits in learning and memory. Effects of the azaindolizinone derivative ZSET1446/ST101, a newly synthesized cognitive enhancer, on cognitive impairment and deposition of amyloid β (Aβ) were assessed in the SAMP8. ZSET1446 was administered in drinking water at estimated doses of 0.002, 0.01, and 0.1 mg/kg per day from the age of 8 months. The SAMP8 at the age of 8 months showed cognitive impairment in a novel object recognition task compared with young SAMP8 at the age of 8 weeks. Further, grading scores were gradually increased from 9 to 12 months and Aβ-like immunoreactivity in the hippocampus was increased at the age of 10 months. ZSET1446 ameliorated cognitive deficits of SAMP8 after 4, 8, 12, and 16 weeks of treatment in a novel object recognition test. ZSET1446 also reduced grading scores of SAMP8 after 16 weeks of treatment. Further, 8-week treatment of ZSET1446 significantly reduced the total number of Aβ-positive granules in the hippocampus. These results suggest that ZSET1446 shows ameliorating effects on SAMP8 partly due to the suppression of an increase of Aβ-deposition in the hippocampus.
衰老加速敏感 8 号小鼠品系（SAMP8）在学习和记忆方面出现与年龄相关的缺陷。评估了新合成的认知增强剂氮茚并吲哚酮衍生物 ZSET1446/ST101 对 SAMP8 认知障碍和淀粉样β（Aβ）沉积的影响。ZSET1446 以饮用水的形式给药，每天的估计剂量为 0.002、0.01 和 0.1mg/kg，从 8 个月大开始。与 8 周龄的年轻 SAMP8 相比，8 月龄的 SAMP8 在新物体识别任务中表现出认知障碍。此外，评分从 9 个月到 12 个月逐渐增加，并且在 10 个月大时海马区的 Aβ样免疫反应性增加。在新物体识别测试中，ZSET1446 在 4、8、12 和 16 周的治疗后改善了 SAMP8 的认知缺陷。ZSET1446 还降低了 16 周治疗后的 SAMP8 分级评分。此外，8 周的 ZSET1446 治疗显著减少了海马区 Aβ阳性颗粒的总数。这些结果表明，ZSET1446 对 SAMP8 的改善作用部分归因于抑制海马区 Aβ沉积的增加。
