Abstract
Rivastigmine is a potent acetyl- and butyrylcholinesterase inhibitor widely used for cognitive improvement in Alzheimer’s disease (AD) therapy. However, dose-limiting adverse effects restrict its tolerability and clinical outcomes. This study explored new combined therapy, in which peripheral cholinergic adverse effects and central cognitive amelioration of rivastigmine were differentiated by a peripheral cholinoceptor antagonist anisodamine. The results demonstrated that rivastigmine (0.75 and 2.0 mg/kg) could significantly reverse the scopolamine-induced cognitive deficit in mice through passive avoidance test. Nevertheless, a high dose of rivastigmine (3.25 mg/kg) would compromise cognitive amelioration and produce obvious adverse effects, including hypersalivation, intestinal hyperperistalsis and muscle cramp. Interestingly, concomitant administration of anisodamine (10 mg/kg) effectively counteracted both the muscarinergic and nicotinergic adverse effects, while facilitating cognitive amelioration of rivastigmine (3.25 mg/kg). These findings provide an insight into the feasibility of combined therapy with cholinesterase inhibitors and peripheral cholinoceptor antagonists for the treatment of AD.
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Acknowledgments
This study was sponsored by the National Natural Science Foundation of China (No. 30772553 and 30701018), the Major Basic Research Project of Shanghai Municipal Science and Technology Commission (07DJ14005) and Research Fund for the Doctoral Program of China Education Ministry (200802480058). We thank Ting Zhang, Yan Qin, Jing-Xia Chen, Yi-Qing Shi and Yan Zhou for their contribution to the experiment on muscle cramp evaluation.
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W.-W. Zhang and Z.-P. Xu contributed equally to this work.
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Zhang, WW., Xu, ZP., Cui, YY. et al. Peripheral cholinoceptor antagonist anisodamine counteracts cholinergic adverse effects and facilitates cognitive amelioration of rivastigmine. J Neural Transm 116, 1643–1649 (2009). https://doi.org/10.1007/s00702-009-0297-7
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DOI: https://doi.org/10.1007/s00702-009-0297-7