Sunitinib, a Clinically Used Anticancer Drug, Is a Potent AChE Inhibitor and Attenuates Cognitive Impairments in Mice.

Abstract

Sunitinib, a tyrosine kinase inhibitor, is clinically used for the treatment of cancer. In this study, we found for the first time that sunitinib inhibits acetylcholinesterase (AChE) at submicromolar concentrations in vitro. In addition, sunitinib dramatically decreased the hippocampal and cortical activity of AChE in a time-dependent manner in mice. Molecular docking analysis further demonstrates that sunitinib might interact with both the catalytic anion and peripheral anionic sites within AChE, which is in accordance with enzymatic activity results showing that sunitinib inhibits AChE in a mixed pattern. Most importantly, we evaluated the effects of sunitinib on scopolamine-induced cognitive impairments in mice by using novel object recognition and Morris water maze tests. Surprisingly, sunitinib could attenuate cognitive impairments to a similar extent as donepezil, a marketed AChE inhibitor used for the treatment of Alzheimer's disease. In summary, our results have shown that sunitinib could potently inhibit AChE and attenuate cognitive impairments in mice.

• Authors: Ling Huang, Jiajia Lin, Siying Xiang, Kangrong Zhao, Jie Yu, Jiacheng Zheng, Daping Xu, Shinghung Mak, Shengquan Hu, Shehani Nirasha, Chuang Wang, Xiaowei Chen, Junfang Zhang, Shujun Xu, Xiaofei Wei, Zaijun Zhang, Dongsheng Zhou, Wenhua Zhou, Wei Cui, Yifan Han, Zhenyu Hu, Qinwen Wang
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 7 Issue 8 Pg. 1047-56 (08 17 2016) ISSN: 1948-7193 [Electronic] United States
• PMID: 27046396 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cholinergic Antagonists
• Cholinesterase Inhibitors
• Indans
• Indoles
• Piperidines
• Pyrroles
• Donepezil
• Scopolamine
• Acetylcholinesterase
• Sunitinib

Topics

• Acetylcholinesterase (metabolism)
• Animals
• Antineoplastic Agents (therapeutic use)
• Cholinergic Antagonists (toxicity)
• Cholinesterase Inhibitors (therapeutic use)
• Cognition Disorders (drug therapy)
• Disease Models, Animal
• Donepezil
• Dose-Response Relationship, Drug
• Exploratory Behavior (drug effects)
• Indans (pharmacology)
• Indoles (therapeutic use)
• Male
• Maze Learning (drug effects)
• Mice
• Mice, Inbred ICR
• Molecular Docking Simulation
• Piperidines (pharmacology)
• Pyrroles (therapeutic use)
• Scopolamine (toxicity)
• Sunitinib