The effect of 5-fluorouracil on the long term survival and proliferation of cells in the rat hippocampus

Abstract

Chemotherapy has been reported to produce cognitive impairments in a significant number of cancer patients. These deficits frequently involve aspects of spatial or declarative memory which can persist for up to several years after completion of the treatment. We have recently shown that 5-fluorouracil (5-FU), a commonly used chemotherapy drug, induces cognitive impairment and a reduction in hippocampal neurogenesis using a rat model of chemotherapy (Elbeltagy et al. [17]). The present study examines the effects of two weeks of 5-FU treatment on cell proliferation in the sub granular zone (SGZ) of the dentate gyrus and the survival of newly dividing cells over a six week period after the end of treatment. Cell proliferation at each time point was quantified by staining for the cell proliferation marker Ki67 while the survival of cells, dividing at the start of treatment, was determined by quantification of BrdU positive cell numbers after pulse labelling with BrdU at the start of drug treatment. The results show that 2 weeks of 5-FU treatment did not significantly reduce cell proliferation in the SGZ immediately after treatment. However cell proliferation was significantly reduced, compared to saline treated controls, two weeks after the end of treatment and remained significantly reduced at 6 weeks. The survival of cells, dividing at the start of treatment, was significantly reduced when quantified immediately after the end of treatment and continued to decline compared with control animals over the following 2 weeks but no further change occurred at 6 weeks. Quantification of COX-2 positive cell numbers in the hippocampus did not correlate with the reduction in cell proliferation or survival suggesting that inflammation is not responsible for these changes. These results demonstrate that 5-FU has delayed and prolonged effects on hippocampal neurogenesis after the end of chemotherapy treatment. This correlates with patient reports of continued cognitive impairment after treatment and indicates that changes in neurogenesis may underlie these effects.