Pirenzepine Reverses Chemotherapy-Induced Peripheral Neuropathy in Mice

Background/Objectives: Mitochondrial dysfunction is a common feature of many peripheral neuropathies and agents that enhance mitochondrial function have potential as pan-neuropathy therapeutics. M1 receptor (M1R) antagonists enhance mitochondrial function and reverse multiple indices of neuropathy in rodents and humans with diabetic neuropathy. The present studies extend evaluation of the M1R-selective antagonist pirenzepine to mouse models of chemotherapy-induced peripheral neuropathy (CIPN), with a primary focus on pain relief. Results: Oxaliplatin-exposed mice developed allodynia to light touch that persisted for months before resolution. Systemic pirenzepine (1 mg/kg/day) starting prior to chemotherapy did not prevent allodynia but accelerated recovery. Topical delivery (4% pirenzepine in hydrogel) to the paw, beginning after onset of allodynia, also accelerated recovery, with efficacy persisting weeks after treatment cessation and accompanied by normalization of paw responses to heat. Allodynia in paclitaxel-exposed mice was also reversed, but not prevented, by systemic or topical pirenzepine, while heat hyperalgesia and nerve conduction slowing were dose-dependently normalized. Efficacy of pirenzepine was not associated with disruption of the cytotoxicity of chemotherapeutics, as pirenzepine did not alter the LD50 of paclitaxel when applied to breast or ovarian cancer tumor lines in vitro. Tumor suppression by a cisplatin/paclitaxel cocktail given to mice seeded with OVCAR-8 ovarian cancer cells was also not impacted by pirenzepine. In contrast, pirenzepine did not prevent or reverse allodynia caused by the proteasome inhibitor bortezomib. Conclusions: These studies position pirenzepine as a novel interventional treatment against established neuropathy caused by taxanes and platin-based agents and may guide design of therapeutic regimens for future clinical studies.