Breast cancer (BC) is the second most common cancer in the United States. The 5-year survival is high at 99% for cancer located only in the breast. The improvement in survival is in part due to adjuvant chemotherapy. Yet, there are chemotherapy-induced cognitive impairments (CICIs) colloquially known as chemobrain. Regardless of survival, it is estimated that up to 75% of patients experience chemobrain during treatment, while 35% will continue to experience cognitive deficits post-treatment. CICIs can persist 10–20 years following treatment and can negatively impact survivor’s quality of life (QOL). BC patients commonly experience anxiety and depression as psychiatric comorbidities. To investigate the effect of chemotherapy on affective behaviors the BC chemotherapy of doxorubicin, cyclophosphamide, and paclitaxel (AC-T) was administered to female mice. Affective behavior testing was conducted at various time points during and after chemotherapy. We did not identify any changes in anxiety or depressive behaviors 24 h post-last AC injection nor 24 h post-last T injection. We saw an increase in anxiety-related behavior one-month following AC-T.
Cognitive testing was assessed one-month after AC-T treatment using the hippocampal-dependent Morris water maze (MWM). MnBuOE, a superoxide dismutase (SOD) mimic, was tested for its potential neuroprotective role. AC-T mice were significantly impaired in spatial memory while AC-T/Mn mice were not. AC-T mice significantly decreased dendritic length in the dentate gyrus (DG) and (Cornus Ammonis 1) CA1 regions of the hippocampus; however, AC-T/MnBuOE maintained dendritic length. Proteomic analysis of hippocampal lysates revealed mitochondrial proteins as significantly affected in both AC-T and AC-T/MnBuOE groups Canonical pathways affected by AC-T treatment included molybdenum cofactor and selenocysteine biosynthesis, fatty acid activation, and the super pathway of inositol phosphate compounds. The comparison between the AC-T and AC-T/MnBuOE revealed sirtuin signaling, mitochondria L-carnitine shuttle pathway, and the superpathway of inositol phosphate compounds to be significantly affected. Altogether, the proteomic results suggest that AC-T is inducing oxidative stress which affects mitochondrial function and energy metabolism. The addition of MnBuOE seems to act on pathways related to mitochondria and metabolism which hint at possible mechanisms behind its ameliorative effect on cognition.
|Advisor:||Allen, Antiño R.|
|Commitee:||Aykin-Burns, Nukhet, Byrum, Stephanie, Hayar, Abdallah, Price, Elvin|
|School:||University of Arkansas for Medical Sciences|
|Department:||Neurobiology and Developmental Science|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 82/7(E), Dissertation Abstracts International|
|Subjects:||Neurosciences, Behavioral psychology|
|Keywords:||Anxiety, Chemobrain, Chemotherapy, Cognition, Depression, MnBuOE|
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