A I Virtanen Institute, Department of Neurobiology, University of Eastern Finland, Kuopio, Finland.
Neuropharmacology. 2011 Oct-Nov;61(5-6):891-9. doi: 10.1016/j.neuropharm.2011.06.008. Epub 2011 Jun 17.
This preclinical study investigated the ability of memantine (MEM) to stimulate brain acetylcholine (ACh) release, potentially acting synergistically with donepezil (DON, an acetylcholinesterase inhibitor). Acute systemic administration of either MEM or DON to anesthetized rats caused dose-dependent increases of ACh levels in neocortex and hippocampus, and the combination of MEM (5 mg/kg) and DON (0.5 mg/kg) produced significantly greater increases than either drug alone. To determine whether ACh release correlated with cognitive improvement, rats with partial fimbria-fornix (FF) lesions were treated with acute or chronic MEM or DON. Acute MEM treatment significantly elevated baseline hippocampal ACh release but did not significantly improve task performance on a delayed non-match-to-sample (DNMS) task, whereas chronic MEM treatment significantly improved DNMS performance but only marginally elevated baseline ACh levels. Acute or chronic treatment with DON (in the presence of neostigmine to allow ACh collection) did not significantly improve DNMS performance or alter ACh release. In order to investigate the effect of adding MEM to ongoing DON therapy, lesioned rats pretreated with DON for 3 weeks were given a single intraperitoneal dose of MEM. MEM significantly elevated baseline hippocampal ACh levels, but did not significantly improve DNMS task scores compared to chronic DON-treated animals. These data indicate that MEM, in addition to acting as an NMDA receptor antagonist, can also augment ACh release; however, in this preclinical model, increased ACh levels did not directly correlate with improved cognitive performance.
本临床前研究旨在探究美金刚（MEM）刺激脑乙酰胆碱（ACh）释放的能力，其可能与多奈哌齐（DON，乙酰胆碱酯酶抑制剂）产生协同作用。在麻醉大鼠中急性全身给予 MEM 或 DON 会剂量依赖性地增加新皮质和海马中的 ACh 水平，且 MEM（5mg/kg）与 DON（0.5mg/kg）联合使用比单独使用任一药物产生的增加更显著。为了确定 ACh 释放是否与认知改善相关，对部分穹窿-海马伞（FF）损伤的大鼠进行了急性或慢性 MEM 或 DON 治疗。急性 MEM 治疗显著提高了海马基线 ACh 释放，但对延迟非匹配样本（DNMS）任务的表现无显著改善，而慢性 MEM 治疗显著改善了 DNMS 表现，仅轻微提高了基线 ACh 水平。急性或慢性 DON 治疗（在新斯的明存在下允许 ACh 收集）对 DNMS 表现或 ACh 释放均无显著改善。为了研究在持续 DON 治疗中添加 MEM 的效果，用 DON 预处理 3 周的损伤大鼠给予单次腹腔 MEM 剂量。MEM 显著提高了海马基线 ACh 水平，但与慢性 DON 治疗动物相比，DNMS 任务评分无显著改善。这些数据表明，MEM 除了作为 NMDA 受体拮抗剂外，还可以增强 ACh 释放；然而，在该临床前模型中，ACh 水平的增加并未直接与认知表现的改善相关。
