F. Javier Alvarez-Leefmans (Committee Member), Timothy Cope (Advisor), David Ladle (Committee Member), Mill Miller (Committee Member), Mark Rich (Advisor)
Doctor of Philosophy (PhD)
Neurotoxicity is one of the most significant side effects diminishing clinical efficacy and patient quality of life during and following chemotherapy. Oxaliplatin (OX) is a platinum based chemotherapy agent used in the treatment of colorectal cancer. Colorectal cancer currently ranks as the 4th most common cancer, and the majority of patients receive OX as a part of their adjuvant therapy. OX based adjuvant therapies significantly improve 5 year survival rates, however in many cases patients must stop treatment early because of the neurotoxic side effects. OX causes two clinically distinct forms of neurotoxicity. Acutely, within hours and for days following OX infusion patients experience positive symptoms including, paresthesia, cold induced pain, and muscle cramping/fasciculation. These symptoms typically subside in between treatments but often worsen with each successive OX infusion. Chronically, with accumulating doses of OX and following treatment cessation, patients experience negative symptoms including numbness, pain, and sensory ataxia. The symptoms persist in a substantial number of patients for years following cessation of chemotherapy and significantly diminish quality of life. While OX neurotoxicity has been widely studied, there are still fundamental gaps in knowledge regarding (a) the mechanisms underlying acute and chronic neurotoxicity, (b) the suggested causal link between acute and chronic OX, and (c) targeted treatment aimed at alleviating the neurotoxic side effects of acute and chronic OX. In order to address these gaps we applied behavioral and in vivo electrophysiological techniques and pharmacological manipulation in chronic OX-treated, acutely OX-treated, and control rats. Building on our recent discovery that following chronic OX-treatment muscle proprioceptors cannot sustain repetitive firing necessary for normal encoding, we hypothesized that loss of proprioceptive signaling should result in behavioral deficits and that impaired encoding results from disruption of persistent inward Na+ currents (NaPIC). Using the methods above we confirmed these hypotheses and have developed a targeted treatment that restores proprioceptive encoding after chronic OX-treatment. Lastly, given the suggested link between acute and chronic neurotoxicity we sought to determine the location of changes in muscle proprioceptor excitability following acute OX-treatment.
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