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Issue 5, 2015
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Computational discovery and experimental verification of tyrosine kinase inhibitor pazopanib for the reversal of memory and cognitive deficits in rat model neurodegeneration

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Abstract

Cognition and memory impairment are hallmarks of the pathological cascade of various neurodegenerative disorders. Herein, we developed a novel computational strategy with two-dimensional virtual screening for not only affinity but also specificity. We integrated the two-dimensional virtual screening with ligand screening for 3D shape, electrostatic similarity and local binding site similarity to find existing drugs that may reduce the signs of cognitive deficits. For the first time, we found that pazopanib, a tyrosine kinase inhibitor marketed for cancer treatment, inhibits acetylcholinesterase (AchE) activities at sub-micromolar concentration. We evaluated and compared the effects of intragastrically-administered pazopanib with donepezil, a marketed AchE inhibitor, in cognitive and behavioral assays including the novel object recognition test, Y maze and Morris water maze test. Surprisingly, we found that pazopanib can restore memory loss and cognitive dysfunction to a similar extent as donepezil in a dosage of 15 mg kg−1, only one fifth of the equivalent clinical dosage for cancer treatment. Furthermore, we demonstrated that pazopanib dramatically enhances the hippocampal Ach levels and increases the expression of the synaptic marker SYP. These findings suggest that pazopanib may become a viable treatment option for memory and cognitive deficits with a good safety profile in humans.

Graphical abstract: Computational discovery and experimental verification of tyrosine kinase inhibitor pazopanib for the reversal of memory and cognitive deficits in rat model neurodegeneration

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Publication details

The article was received on 06 Nov 2014, accepted on 12 Jan 2015 and first published on 13 Jan 2015


Article type: Edge Article
DOI: 10.1039/C4SC03416C
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Citation: Chem. Sci., 2015,6, 2812-2821
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    Computational discovery and experimental verification of tyrosine kinase inhibitor pazopanib for the reversal of memory and cognitive deficits in rat model neurodegeneration

    Y. Yang, G. Li, D. Zhao, H. Yu, X. Zheng, X. Peng, X. Zhang, T. Fu, X. Hu, M. Niu, X. Ji, L. Zou and J. Wang, Chem. Sci., 2015, 6, 2812
    DOI: 10.1039/C4SC03416C

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