Yabuki Yasushi, Matsuo Kazuya, Hirano Koga, Shinoda Yasuharu, Moriguchi Shigeki, Fukunaga Kohji
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Pharmacology. 2017;99(3-4):160-171. doi: 10.1159/000452839. Epub 2017 Jan 4.
Memantine, an uncompetitive N-methyl-D-aspartate receptor antagonist, and the cholinesterase inhibitor, donepezil, are approved in most countries for treating moderate-to-severe Alzheimer's disease (AD). These drugs have different molecular targets; thus, it is expected that the effects of combined treatment would be synergistic. Some reports do show memantine/donepezil synergy in ameliorating cognition in AD model animals, but their combined effects on behavioral and psychological symptoms of dementia (BPSD)-like behaviors have not been addressed. Here, we investigate combined memantine/donepezil effects on cognitive impairment and BPSD-like behaviors in olfactory bulbectomized (OBX) mice. Interestingly, combined administration synergistically improved both depressive-like behaviors and impaired social interaction in OBX mice, whereas only weak synergistic effects on cognitive performance were seen. To address mechanisms underlying these effects, we used in vivo microdialysis study and observed impaired nicotine-induced serotonin (5-HT) release in OBX mouse hippocampus. Combined memantine/donepezil administration, but not single administration of either, significantly antagonized the decrease in nicotine-induced 5-HT release seen in OBX mouse hippocampus. Furthermore, decreased autophosphorylation of calcium/calmodulin dependent protein kinase II (CaMKII) was rescued in hippocampal CA1 and dentate gyrus of OBX mice by combined memantine/donepezil administration. These results suggest that improvement of BPSD-like behaviors by the co-administration of both drugs is in part mediated by enhanced 5-HT release and CaMKII activity in OBX mouse hippocampus.
美金刚是一种非竞争性N-甲基-D-天冬氨酸受体拮抗剂，胆碱酯酶抑制剂多奈哌齐在大多数国家被批准用于治疗中重度阿尔茨海默病（AD）。这些药物有不同的分子靶点；因此，预计联合治疗的效果将具有协同作用。一些报告确实显示美金刚/多奈哌齐在改善AD模型动物认知方面具有协同作用，但它们对痴呆行为和心理症状（BPSD）样行为的联合作用尚未得到研究。在这里，我们研究了美金刚/多奈哌齐联合用药对嗅球切除（OBX）小鼠认知障碍和BPSD样行为的影响。有趣的是，联合给药协同改善了OBX小鼠的抑郁样行为和受损的社交互动，而对认知能力的协同作用较弱。为了探究这些作用的潜在机制，我们进行了体内微透析研究，观察到OBX小鼠海马中尼古丁诱导的血清素（5-HT）释放受损。美金刚/多奈哌齐联合给药，而非单独给药，显著拮抗了OBX小鼠海马中尼古丁诱导的5-HT释放的减少。此外，联合使用美金刚/多奈哌齐可使OBX小鼠海马CA1区和齿状回中钙/钙调蛋白依赖性蛋白激酶II（CaMKII）的自磷酸化减少得到恢复。这些结果表明，两种药物联合给药对BPSD样行为的改善部分是由OBX小鼠海马中5-HT释放增强和CaMKII活性增强介导的。
