Combined Memantine and Donepezil Treatment Improves Behavioral and Psychological Symptoms of Dementia-Like Behaviors in Olfactory Bulbectomized Mice.
Combined Memantine and Donepezil Treatment Improves Behavioral and Psychological Symptoms of Dementia-Like Behaviors in Olfactory Bulbectomized Mice.
复制标题
美金刚和多奈哌齐联合治疗可改善嗅球切除小鼠的痴呆样行为的行为和心理症状。
DOI：
10.1159/000452839
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发表时间：
2017
期刊：
影响因子：
3.1
通讯作者：
Fukunaga K.
中科院分区：
文献类型：
--
作者：
Yabuki Y;Matsuo K;Hirano K;Shinoda Y;Moriguchi S;Fukunaga K.
美金刚（一种非竞争性N-甲基-D-天冬氨酸受体拮抗剂）和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度至重度阿尔茨海默病（AD）。这些药物具有不同的分子靶点;因此，预计联合治疗的效果将是协同的。一些报道确实显示美金刚/多奈哌齐在改善AD模型动物的认知方面具有协同作用，但它们对痴呆（BPSD）样行为的行为和心理症状的联合作用尚未得到解决。在这里，我们研究了联合美金刚/多奈哌齐对嗅球切除（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会互动，而对认知表现的协同作用很弱。为了解决这些影响的机制，我们使用在体内微透析研究，并观察受损的尼古丁诱导的5-羟色胺（5-HT）释放OBX小鼠海马。联合美金刚/多奈哌齐给药，但不是单次给药，显着拮抗尼古丁诱导的5-HT释放在OBX小鼠海马中看到的减少。此外，降低钙/钙调蛋白依赖性蛋白激酶II（CaMK II）的自磷酸化的救援在海马CA 1和齿状回的OBX小鼠联合美金刚/多奈哌齐管理。这些结果表明，通过共同施用两种药物来改善BPSD样行为部分地由OBX小鼠海马中增强的5-HT释放和CaMKII活性介导。
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.