Figure 1: New neuron (green) in the
brain; nuclei in red.
Adult neurogenesis is the creation of new brain cells, called neurons, in adulthood. It occurs in all mammals studied to date including rodents, non-human primates, and humans. The new neurons play a role in acquisition of certain types of memory and possibly in regulation of mood. Chemotherapy treatments, such as 5-fluorouracil (5FU), induce memory deficits in patients, which persist long after treatment is completed. In conjunction with this, the treatments also reduce the number of new brain cells created during adulthood. Annabelle Chambers, a 3rd year PhD candidate in Dr. Peter Wigmore's lab at the University of Nottingham is studying potential ways to protect against the reduction of new cells associated with 5FU treatment.
As part of her dissertation research, Annabelle used rats to investigate the effects of fluoxetine (aka Prozac) pretreatment on the creation of new cells in the hippocampus with 5FU treatment. First, she looked at the effects of acute (short-term) 5-FU treatment. Rats were given either fluoxetine in their drinking water or untreated water for 20 days. Then they received injections of either 5FU and leucovorin, a drug used to enhance 5FU's effectiveness, or saline. The animals were allowed to recover either one day or one week after treatment. The cell marker Ki67 was used to detect cells that were currently dividing, the defining characteristic of new cells.
Rats that received only 5FU had a significantly reduced number of new cells when compared with rats that received saline injections. Animals that received fluoxetine prior to 5FU injections were protected from this decrease and had a similar number of new cells compared with saline-injected rats. If the animals given 5FU were given a week to recover after treatment, the number of new cells was not significantly different from saline-injected controls, which shows that the recovery time after treatment is helpful.
In the second part of her study, she created a study design more similar to 5FU treatment in humans. That is, the animals were pretreated with either fluoxetine or regular drinking water for 20 days and then received five injections of 5FU and leucovorin every other day. They were allowed to recover for one week. In this chronic paradigm, even after 1 week of recovery the rats that received 5FU only had reduced numbers of new cells compared with each of the other groups: control (only saline), control (only fluoxetine), and 5FU + fluoxetine. The animals that had fluoxetine pre-treatment before 5FU had a similar number of cells as both control groups.
The results suggest that fluoxetine, which has its own proliferative stimulating effects, can provide a protective effect for the cell damaging effects of 5FU treatment if given prior to treatment. Annabelle said treatment with fluoxetine after 5FU treatment does not have an effect on proliferation though the data was not included in this poster. The relevance to behavior has already been shown in Dr. Wigmore's lab as well: animals treated with fluoxetine prior to 5FU treatment do not show the cognitive deficits shown by animals treated with only 5FU. Annabelle will continue to nail down the mechanism using additional proliferation assays and in vitro (cell culture) work as she continues her graduate research.