Date of Award
12-1-2024
Degree Name
Doctor of Philosophy
Department
Molecular, Cellular, and Systemic Physiology
First Advisor
Cheatwood, Joseph
Abstract
Chemotherapy is one of the widely used treatments for patients with cancer. It has been proven as an effective therapy to lengthen the survival of cancer patients and improve their quality of life. However, more than half of the cancer survivors suffer from cognitive deficits following chemotherapy, which is termed “Chemo brain”. There is ample evidence on the side effects of chemo drugs, the mechanisms of which seem to be ambiguous. Doxorubicin (DOX) is a cytotoxic anthracycline antibiotic reported to induce chemo-brain via DNA damage, disruption of hippocampal neurogenesis, oxidative stress, inflammation, and dysregulation of apoptosis. Cannabinoids have been studied in various neurological disorders. Cannabidiol (CBD) is a non-psychoactive component of Cannabis sativa that has been identified as a possible therapeutic agent against many neurodegenerative disorders. However, studies regarding the neuroprotection of CBD against chemo-brain remain obscure. The study's long-term goal is to provide mechanistic targets for future therapeutics to treat cognitive deficits arising after chemotherapy treatment. To accomplish the goals above, Female Long Evans Hooded rats received intraperitoneal injections of DOX (6mg/kg) or vehicle (0.9% saline) once a week for four weeks, followed by oral administration of CBD (10mg/kg) three times a week for the same period. Elevated Plus Maze Test, Open Field Test, Marble Burying Test, Novel Object Recognition, and the Sucrose Preference Test were performed to assess anxiety and depression-like behaviors, respectively. Additionally, the String-pulling and Bar-walk tests were performed to assess motor functions. Brain tissues isolated from Dox and CBD-treated rats were processed for gene expression analysis of markers of neuroinflammation and neurogenesis. CBD was significantly protective against Dox-induced anxiety and depression-like behaviors as measured by several behavioral tests. Furthermore, CBD improved DOX-induced alterations of gene expression of biomarkers of neuroinflammation in the hippocampus and prefrontal cortex. This provides insights into future studies on possible mechanisms by which CBD could alleviate Dox-induced cognitive dysfunction.
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