Spatial memory deficits in mice induced by chemotherapeutic agents are prevented by acetylcholinesterase inhibitors

Purpose 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. Methods 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. Results 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. Conclusions 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.