Neuropathy Due to Amiodarone: Schwann Cells Are the Target (P06.138)

Abstract

Objective: This study evaluated the pathophysiology of amiodarone-induced peripheral neuropathy both in vivo and in vitro. Background Amiodarone has been long known to cause peripheral neuropathy, but the mechanism of action is uncertain. Design/Methods: We performed mouse dorsal root ganglia neuronal and Schwann cell cultures exposed to a dose range of amiodarone or placebo. We examined cellular viability, reactive oxygen species and mitochondrial function in vitro. Complementary in vivo studies with either systemic (intraperitoneal), intrathecal or near-nerve amiodarone or placebo delivery were performed in mice. Electrophysiological, structural and molecular studies were performed for dorsal root ganglia and sciatic nerves after 3 months of exposure to amiodarone or placebo. Results: There was no impact upon in vitro neurons with exposure to amiodarone. However, amiodarone was associated with a dose-related loss of Schwann cells in vitro, poor outcomes of myelination, and mitochondrial dysfunction. In vivo, amiodarone had mild impact when delivered intrathecally or systemically, but led to marked localized changes in nerve structure when delivered locally at the sciatic nerve. Local amiodarone produced slowing of nerve conduction velocities, loss of motor and sensory nerve potential amplitudes, and led to extensive myelin thinning and loss of large nerve fibers. Reactive oxygen species and mitochondrial dysfunction were detected in the local sciatic nerve with amiodarone delivery. Conclusions: Amiodarone appears to have a direct impact upon Schwann cells and their myelination function rather than any direct effect upon neuronal cells. Amiodarone–induced experimental peripheral neuropathy is a pure demyelinating neuropathy with direct effects upon Schwann cell well being. Supported by: Alberta Heritage Foundation for Medical Research. Disclosure: Dr. Hohol has nothing to disclose. Dr. Jawad has nothing to disclose. Dr. Ayer has nothing to disclose. Dr. Toth has received personal compensation for activities with Pfizer and Eli Lilly & Company as a speaker. Dr. Toth has received research support from Pfizer Inc, Valeant Pharmaceuticals International and Eli Lilly & Company.