Date of Award

5-2014

Level of Access Assigned by Author

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology

Advisor

Thane E. Fremouw

Second Committee Member

Shawn W. Ell

Third Committee Member

Marie J. Hayes

Abstract

“Chemo fog” is a phenomenon in which cancer survivors treated with chemotherapy drugs experience long-term cognitive deficits years after chemotherapy treatment. Although these impairments generally appear to be mild to moderate in nature, they can persist for many years after the completion of treatment, and have a dramatic negative impact on patient quality of life. Additionally, it is unclear what the neurobiological mechanism underlying chemo fog is, though both animal and human literature suggest that white matter damage may be at play. My thesis investigates the neurobiological underpinnings of chemo fog, in the hopes of finding a way to reduce and/or prevent these cognitive symptoms. These studies utilize a male C57BL/6J mouse model to evaluate a number of chemotherapy drugs and their potentially demyelinating effects (within the corpus callosum) at various time points following administration, as well as the potentially protective properties of a number of neuroprotective agents. EXP 1 : The effects of single agent cyclophosphamide or doxorubicin were evaluated at 56 days and 6 months post treatment, indicating no changes following cyclophosphamide at either time point, but doxorubicin did lead to delayed demyelination at 6 months post treatment. EXP 2: The long-term effects of single agent 5-fluorouracil (5-FU) on myelin having already been established at these same time points (Han et al., 2008), 5-FU in combination with either antioxidants melatonin, or NAC, or antidepressant fluoxetine were compared to controls and 5-FU treated animals independently. The results show no indication of demyelination following 5-FU, nor neuroprotection effects of any protective agent. EXP 3: Extreme long-term effects of combination cyclophosphamide & doxorubicin or single agent 5-FU in animals previously evaluated in a behavioral study were assessed at 14 months post treatment. Both groups showed significant demyelination. EXP 4: Pilot data was collected evaluating demyelination 14 months following 5-FU and melatonin administration, indicating a trend for demyelination following 5-FU treatment compared to controls, and no evidence of melatonin neuroprotection. These studies suggest that, while the specific point at which it is first apparent may vary, administration of 5-FU or doxorubicin leads to delayed demyelination.

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