Yanai Shuichi, Semba Yuki, Ito Hideki, Endo Shogo
Aging Neuroscience Research Team, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0015, Japan.
Psychopharmacology (Berl). 2014 Jul;231(13):2681-93. doi: 10.1007/s00213-014-3442-4. Epub 2014 Jan 25.
Phosphodiesterases (PDEs) play an important role in the regulation of intracellular signaling mediated by cyclic adenosine monophosphate (cAMP). Recently, several PDE inhibitors were assessed for their possible cognitive enhancing properties. However, little is known about the effect of PDE3 inhibitors on memory function.
We examined how the PDE3 inhibitor cilostazol affects C57BL/6 J mice as they perform various behavioral tasks. After behavioral assessment, brains of the mice were analyzed immunohistochemically to quantify the phosphorylation of cAMP-responsive element binding protein (CREB), a downstream component of the cAMP pathway.
Oral administration of cilostazol significantly enhanced recollection of the exact platform location in the Morris water maze probe test. Cilostazol also improved context-dependent long-term fear memory, without affecting short-term memory. No apparent effect was observed in cue-dependent fear memory. The results suggest that cilostazol selectively improves hippocampus-dependent long-term memory in these tasks. Cilostazol also significantly increased the number of phosphorylated-CREB-positive cells in hippocampal dentate gyrus.
These results suggest that cilostazol may exert its beneficial effects on learning and memory by enhancing the cAMP system in hippocampus, where it increases intracellular cAMP activity.
磷酸二酯酶（PDEs）在由环磷酸腺苷（cAMP）介导的细胞内信号传导调节中发挥重要作用。最近，几种PDE抑制剂被评估其可能的认知增强特性。然而，关于PDE3抑制剂对记忆功能的影响知之甚少。
我们研究了PDE3抑制剂西洛他唑在C57BL/6 J小鼠执行各种行为任务时的作用。行为评估后，对小鼠大脑进行免疫组织化学分析，以量化cAMP反应元件结合蛋白（CREB）的磷酸化水平，CREB是cAMP通路的下游成分。
口服西洛他唑显著增强了莫里斯水迷宫探针试验中对确切平台位置的记忆。西洛他唑还改善了情境依赖性长期恐惧记忆，而不影响短期记忆。在线索依赖性恐惧记忆中未观察到明显影响。结果表明，西洛他唑在这些任务中选择性地改善了海马依赖性长期记忆。西洛他唑还显著增加了海马齿状回中磷酸化CREB阳性细胞的数量。
这些结果表明，西洛他唑可能通过增强海马中的cAMP系统对学习和记忆产生有益作用，在海马中它增加细胞内cAMP活性。
