UC San Diego

Chemotherapy induced peripheral neuropathy (CIPN) is a debilitating condition that affects up to 70% of patients undergoing chemotherapy treatment. CIPN causes a mix of small and large fiber damage as well as motor dysfunction that occurs less frequently but varies patient to patient. CIPN is categorized as a “dying-back” axonal degeneration in which neurodegeneration proceeds in a distal-to-proximal manner. There is currently no FDA-approved prophylactic or treatment for CIPN. In vitro research has shown that rat sensory neurons exposed to chemotherapeutics exhibited reduced neurite outgrowth, but neurons that were concurrently exposed to the muscarinic acetylcholine receptor 1 (M1R) antagonist pirenzepine (PZ) were protected from chemotoxicity. To investigate the practical application of this effect, indices of CIPN were measured in Swiss Webster mice treated with chemotherapeutics paclitaxel, oxaliplatin, and bortezomib. Subcutaneous PZ treatment prevented and reversed indices of neuropathy and neuropathic pain in each drug class. The translational therapeutic potential of PZ was explored by testing varied routes of administration and dose frequencies. Topical PZ had no effect on transient tactile allodynia but was able to reverse MNCV slowing in mice with paclitaxel induced CIPN. Dose frequency was examined as a possible variable in topical PZ efficacy. Topical PZ reversed tactile allodynia at each dose frequency and reversed mild MNCV slowing. My data suggests that M1R may be a viable target in preventing and reversing CIPN.