Improvements in cancer therapy have helped a growing number of patients to survive. Chemotherapy is the most commonly implemented treatment. One such chemotherapeutic agent, 5-fluorouracil (5-Fu), has been associated with cognitive impairments in patients for a multitude of cancers following the cessation of treatment. Leucovorin (LV), a reduced folic acid, is often given in conjunction with 5-Fu to exacerbate the antineoplastic effects. Since several chemotherapeutic agents are often administered together, there is a need to examine their independent and combined effects on cognition. This dissertation focuses on how 5-Fu affects the hippocampus, a brain structure involved in long-term memory functions. Following 5-Fu treatment in mice, morphological characteristics of the hippocampus were quantified using the Golgi-cox method. Neuronal dendrites within the dentate gyrus (DG), Cornu Ammonis 1 (CA1), and Cornu Ammonis 3 (CA3) were significantly less complex following 5-Fu administration. Dendritic morphology and branching variations within the hippocampus are implicated in cognition and memory formation, with alterations in complexity associated with pathophysiological and behavioral changes. In an attempt to understand how 5-Fu mediates cytokine and chemokine responses, 14 analytes were measured at the same time that Golgi samples were taken. 8 analytes were significantly elevated following 5-Fu treatment. In clinical studies, an increase in cytokine levels following chemotherapy treatment has been associated with cognitive dysfunction. After establishing that 5-Fu treatment lead to changes in dendritic complexity and cytokine expression, behavioral tests were performed to determine if 5-Fu administered alone or co-administered with LV would have an effect on cognition. Spatial memory deficits were observed in mice following 5-Fu and 5-Fu/LV treatment in mice. Immunohistochemical staining for activated microglia and blood vessel endothelial cells were also performed, as chemotherapeutic treatment has been shown to increase neuroinflammation and change blood circulation. We found that there was not an increase in activated microglia following chemotherapeutic treatment. However, there was a significant reduction in blood vessel length. This alteration in the neurovasculature may contribute to cognitive impairments, as even slight changes in cerebral blood flow can have negative long-term effects.
|Commitee:||Crooks, Peter, Garcia-Rill, Edgar, Hayar, Abdallah, Pierce, Dwight|
|School:||University of Arkansas for Medical Sciences|
|Department:||Neurobiology and Developmental Science|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Subjects:||Neurosciences, Animal sciences|
|Keywords:||5-fluorouracil, Chemobrain, Cognition, Golgi-cox, Hippocampus, Neurovasculature|
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