Abstract
The chemotherapy drug, 5-fluorouracil (5-FU), has been reported to cause cognitive impairments in cancer patients. The drug also reduces cell proliferation and survival in the brain. Asiatic acid (AA) is a triterpene compound found in Centella asiatica that can protect against reduction of neurogenesis in the hippocampus and memory deficits induced by valproic acid (VPA). In the present study, we investigated the preventive effects of AA on the deficits in spatial working memory and cell proliferation and survival caused by 5-FU chemotherapy in a rat model. Male Sprague Dawley rats received 5-FU (5 i.v. injections, 25 mg/kg) on day 8, 11, 14, 17 and 20 of the study. This was co-administered with AA (30 mg/kg, oral gavage tube) either 20 days before receiving 5-FU (preventive), after receiving 5-FU (recovery), or for the entire period of the experiment (throughout). Spatial working memory was determined using the novel object location (NOL) test and hippocampal cell proliferation and survival of dividing cells were quantified using immunohistochemistry. Rats in the 5-FU alone and recovery groups showed memory deficits in the NOL test and reductions in cell proliferation and cell survival in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Rats in the control, AA alone, and both preventive and throughout co-administration groups, however, did not exhibit these characteristics. The results showed that 5-FU chemotherapy impaired memory and reduced cell proliferation and cell survival in the SGZ of the hippocampal dentate gyrus. However, these impairments in the animals receiving 5-FU chemotherapy were restored to control levels when AA was co-administered before and during 5-FU treatment. These data demonstrate that AA can prevent the spatial working memory and hippocampal neurogenesis impairments caused by 5-FU chemotherapy.
Highlights
Chemotherapy drugs are widely used to treat cancer patients, including those suffering from breast cancer
There were no significant differences among the six groups regarding to exploration time for either object in the arena, indicating that the animals did not display a preference for either object’s location over the other
Animals treated with 5-FU alone and 5-FU with Asiatic acid (AA) could not discriminate between the object placed in the novel location and that in the familiar location, suggesting that 5-FU induced a deficit in spatial working memory
Summary
Chemotherapy drugs are widely used to treat cancer patients, including those suffering from breast cancer. Previous studies have found that 5-FU treatment induces cognitive deficits, including impairments in attention, visual memory, and speed of information processing [5,6,7]. This drug can cross the blood-brain barrier through simple diffusion and is able to disrupt cell proliferation by blocking the enzyme thymidylate synthase (TS). This enzyme is required for DNA replication [8], which is associated with cell proliferation
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