Date of Degree

5-2018

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Karen Hubbard

Committee Members

Mark Emerson

Jonathan Levitt

Pat Rockwell

Tim Ahles

Subject Categories

Biology | Molecular and Cellular Neuroscience

Keywords

Chemotherapy, Cognition, Cancer, Oxidative Stress, Signal Transduction

Abstract

Systemic chemotherapy treatment is associated with long-term cognitive impairment in breast cancer survivors. While many studies have established the forms of cognition and corresponding regions in the brain most affected, very little is revealed about the potential molecular mechanisms that mediate these changes. The effects of systemic treatment on the brain is likely attributed to many different mechanisms including oxidative stress and immune dysregulation. Earlier studies from our lab have investigated the effects of the chemotherapy cocktail doxorubicin and cyclophosphamide (AC Chemotherapy) in an ovariectomized menopause animal model of ‘chemo brain’ (Salas-Ramirez et al., 2015). We observed that animals injected with these drugs over a period of three weeks demonstrate deficits in some forms of hippocampal- mediated memory which correlates with enhanced basal signaling activity and altered levels synaptic protein expression in the brain. Considering the integral role of BDNF (brain derived neurotrophic factor) on several processes in the CNS and the relationship between the levels of the neurotrophin and cognitive performance, we evaluated the expression of the ligand and its cognate receptor TrkB. Although the levels of BDNF were unaffected after chemotherapy in the hippocampus and prefrontal cortex (PFc), evidence from these studies indicate that systemic treatment is associated with the differential activation and expression of the TrkB receptor isoforms in the two brain regions.

The mRNA and protein product expression of a panel of immediate early genes (arc/arg3.1, bdnf, cfos, cjun, creb, homer1a) were also evaluated in the brain. These IEGs have been documented to have important roles in learning and memory, survival, and the cellular stress response. AC chemotherapy led to altered phosphorylation and expression of several IEG proteins in the brain relative to saline controls. There is growing evidence that the effects of chemotherapy on the CNS may be due in part to inflammation and oxidative stress. We addressed these hypotheses by examining whether the levels of pro-inflammatory cytokines and oxidative stress responsive gene markers were altered in the CNS of rats treated with systemic AC chemotherapy. Ultimately our results indicate that an induction of inflammation and increased MAPK signaling is accompanied by oxidative damage to nucleic acids, suggesting that these effects could be linked to the chemotherapy-associated cognitive changes.

The role of oxidative stress and altered intracellular signaling is also addressed in an in vitro cellular model of doxorubicin-induced neurotoxicity using primary hippocampal neurons. The results of these studies indicate that doxorubicin induces caspase 3 -dependent apoptosis and these neurotoxic effects of doxorubicin are associated with the generation of ROS and oxidative damage. Furthermore, we present results that doxorubicin impairs BDNF-mediated signaling to the translational machinery and the subsequent induction of the plasticity associated protein arc/arg3.1, an effect mediated by neuronal oxidative status. All together the results presented in this dissertation provide strong evidence that the effects AC chemotherapy, and in particular doxorubicin, is associated with oxidative damage and a global stress response that may underlie the adverse alterations on the molecular signature of the brain.

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