Naik Runa S, Hartmann Joachim, Kiewert Cornelia, Duysen Ellen G, Lockridge Oksana, Klein Jochen
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, 1300 Coulter Dr, Amarillo, TX 79106, USA.
J Pharm Pharm Sci. 2009;12(1):79-85. doi: 10.18433/j3mk59.
Alzheimer s disease is characterized by a dysfunction of central cholinergic systems and is treated by inhibitors of acetylcholinesterase (AChE). This study tests the effect of two AChE inhibitors in therapeutic use, rivastigmine and donepezil, in mice that are devoid of AChE (AChE-/- mice). Rivastigmine is an inhibitor of both AChE and butyrylcholinesterase (BChE) whereas donepezil is a selective inhibitor of AChE.
We have used in vivo microdialysis to investigate the effects of the two drugs on the extracellular concentration of acetylcholine (ACh) in the hippocampus of AChE-/- mice.
Extracellular ACh levels in the hippocampus were 30-fold elevated in AChE-/- mice compared to wild-type (AChE+/+) animals. Infusion of rivastigmine (1 and 10 microM) caused a further doubling of ACh levels in AChE-/- mice within 90-120 min. In contrast, infusion of donepezil (1 microM) did not affect hippocampal ACh levels in AChE-/- mice although it increased ACh levels more than twofold in wild-type mice.
In the absence of AChE, rivastigmine enhances the levels of extracellular ACh by inhibiting BChE. This finding may be of therapeutic relevance because BChE activity is preserved, but AChE activity is strongly decreased, in late-stage Alzheimer s disease.
阿尔茨海默病的特征是中枢胆碱能系统功能障碍，可通过乙酰胆碱酯酶（AChE）抑制剂进行治疗。本研究测试了两种临床使用的AChE抑制剂，卡巴拉汀和多奈哌齐，对缺乏AChE的小鼠（AChE-/-小鼠）的影响。卡巴拉汀是AChE和丁酰胆碱酯酶（BChE）的双重抑制剂，而多奈哌齐是AChE的选择性抑制剂。
我们使用体内微透析技术研究这两种药物对AChE-/-小鼠海马中乙酰胆碱（ACh）细胞外浓度的影响。
与野生型（AChE+/+）动物相比，AChE-/-小鼠海马中的细胞外ACh水平升高了30倍。注入卡巴拉汀（1和10微摩尔）使AChE-/-小鼠的ACh水平在90-120分钟内进一步翻倍。相比之下，注入多奈哌齐（1微摩尔）对AChE-/-小鼠的海马ACh水平没有影响，尽管它使野生型小鼠的ACh水平增加了两倍多。
在缺乏AChE的情况下，卡巴拉汀通过抑制BChE提高细胞外ACh水平。这一发现可能具有治疗意义，因为在晚期阿尔茨海默病中，BChE活性得以保留，但AChE活性大幅降低。
