Prevention and treatment of paclitaxel-induced peripheral neuropathy

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Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition with potentially devastating effects on large numbers of cancer patients. According to the Centers for Disease Control and Prevention, 650,000 patients are treated with chemotherapy every year in the United States, and between 30- 70% of these patients will develop symptoms of CIPN. Clinical research has demonstrated CIPN is a leading cause of therapeutic non-compliance, reduced quality of life and poorer cancer survival rates. Patients who develop symptomatic CIPN also have an associated $20,000 increase in overall treatment cost in comparison to patients that do not develop symptoms and are also more like to suffer relapse of their cancer. Currently, there are no established treatments for CIPN. We propose that 4-aminopyridine (4AP), principally a K+ channel inhibitor, is a promising candidate to prevent and/or treat CIPN. Separate from the known abilities of 4AP to enable impulse conduction in axons with myelin damage, 4AP has recently been used to treat acute peripheral nerve injuries with enhanced durable functional recovery and repair of myelin damage. In more recent studies, treatment of acute skin wounds with 4AP enhances healing and regeneration of neural elements of skin. In addition, in its best studied applications, 4AP is used to provide symptomatic relief in a variety of neurological syndromes in which normal nerve cell function is compromised. Restoring normal nerve function may also be relevant to decreasing neuropathic pain, as seen in previous studies in individuals with chronic spinal cord injury. The over-arching hypothesis of this proposal is that 4AP can be used to prevent or decrease caused by exposure to paclitaxel (PTX). Our experiments will test the independent sub-hypotheses that (i) initiation of 4AP treatment prior to establishment of CIPN prevents its development without compromising the effectiveness of PTX in treating a well-accepted syngeneic model of breast cancer in mice; and (ii) established CIPN is responsive to 4AP as a means of decreasing neuropathic pain after CIPN is established. An established mouse model for PTX-induced CIPN will be used in these experiments. 4AP will be studied both as a concurrent treatment with PTX to prevent CIPN development, and as a means of providing symptomatic relief in established CIPN. Outcomes will evaluate the pressure sensitivity (allodynia), thermal sensitivity, gait coordination, electrophysiology, muscle physiology, and histology focusing on the ultrastructural changes.