Spatial memory deficits in mice induced by chemotherapeutic agents are prevented by acetylcholinesterase inhibitors
These studies determined whether the acetylcholinesterase inhibitors, donepezil and galantamine, both of which are approved for the treatment of cognitive deficits in Alzheimer’s disease, can prevent or reverse spatial memory deficits in mice induced by cyclophosphamide and doxorubicin, cytotoxic agents commonly used to treat breast cancer.
Female BALB/C mice were trained in the Morris water maze to identify the location of a submerged platform, and, following baseline assessment of spatial memory, received injections of cyclophosphamide and doxorubicin once per week for 4 weeks to impair spatial memory. Saline or acetylcholinesterase inhibitors were administered daily either concurrent with the chemotherapy injections (prevention) or beginning 1 week following the final chemotherapy injections (reversal), and spatial memory was assessed weekly.
Spatial memory declined during and following weekly injections of cyclophosphamide and doxorubicin, and was unaltered when the acetylcholinesterase inhibitors were administered following the manifestation of chemotherapy-induced deficits. In contrast, spatial memory of mice receiving the acetylcholinesterase inhibitors concurrent with chemotherapy did not differ from that at baseline.
Results indicate that chemotherapy-induced spatial memory deficits in mice can be prevented, but not reversed by the use of acetylcholinesterase inhibitors concomitant with chemotherapy, suggesting that these agents should be investigated further for the prevention of chemobrain.
KeywordsChemobrain Cyclophosphamide Donepezil Doxorubicin Galantamine
The authors would like to thank April Lindon for her technical assistance during this study and Dr. Heather Jim for her valuable suggestions and feedback.
These studies were supported in part by USF Research and Innovation Proposal Enhancement Grant and the American Cancer Society Institutional Research Grant, Moffitt Cancer Center.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The care and use of animals were approved in accordance with guidelines set by the University of South Florida Institutional Animal Care and Use Committee, the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines of the National Centre for the Replacement, Refinement and Reduction of Animals in Research.
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