| Patients with cancer are living longer due to the increased application of systemic chemotherapeutic agents. Therefore long-term side effects such as changes in cognition are becoming more prominent in patient care. Very little is known about the mechanism underlying these changes, or even the cells that are affected. Our laboratory has previously shown that chemotherapy decreases neural progenitor cell division and increases cell death in the mouse (Dietrich et al. 2006; Han et al. 2007). This investigation contributes to the previous work exploring the effects of chemotherapeutic agents in the brain. Mice were treated with cisplatin, 5-fluorouracil (5-FU), vincristine or cyclophosphamide. Progenitor cells in the subventricular zone, rostral migratory stream, olfactory bulb, corpus callosum, dentate gyrus, and olfactory epithelium were examined. Progenitor cells were immunolabeled and cells positive for proliferative or cell death markers were counted. In all regions examined, there was a significant decrease in progenitor cell numbers. We also found that erythropoietin (EPO) acts as a neuroprotectant in the brain. When this agent was co-administered with chemotherapeutic agents, EPO was found to prevent the adverse effects on progenitor cells in the brain. Finally, behavioral performance was tested using operant conditioning fixed-interval schedules of reinforcement at the time-points similar to those used in the immunohistochemistry studies. Both cisplatin and 5-FU were found to significantly decrease performance in comparison to vehicle. This decrease in performance was ameliorated with erythropoietin co-administration. This investigation builds on the understanding of the cells affected and behavioral changes due to cancer treatment and could contribute to developing treatments to prevent the neurotoxic side effects of chemotherapy and improving quality of life in recipients of this therapy. |
