Repeated exposure to pyrrolidine-dithiocarbamate induces peripheral nerve alterations in rats

Abstract

Pyrrolidine-dithiocarbamate (PDTC), a synthetic compound widely used in cell biological investigations, recently attracted considerable interest as a putative anticancer agent. However, different dithiocarbamates have previously shown to cause neurological symptoms and morphological alterations in peripheral nerves. The purpose of the present study was to determine whether a 15-day oral administration with low doses of PDTC may produce adverse effects in peripheral nerves of rats. Female Wistar rats were assigned to receive PDTC [0.1, 0.5 or 1.0 mmol/(kg body weight/day)] by gavage for 15 days. Reduced conduction velocity was observed by electrophysiological analysis in tibial nerves of treated animals, accompanied by a marked decrease in Shwann cell S100-protein expression determined by immunohistochemistry. Electron microscopy evaluation revealed marked myelin degeneration in the fibers of treated animals. In particular, both morphological and electrophysiological data suggested an impairment of large, fast conducting fibers, whereas the smallest and slowest ones remained intact. However, the activity of plasma and liver alkaline-phosphatase, an enzymic marker of hepatic dithiocarbamate toxicity, was not altered by the treatment. The total contents of the redox-active metal copper increased in tibial nerves of treated rats and was accompanied by raised levels of lipid peroxidation products. This finding suggests a role for oxidative stress in the development of PDTC-induced pathological and functional alterations of tibial nerves. The observation that a 15-day treatment with low doses of PDTC causes functional and morphological derangement of peripheral nerves advices against the possible use of this compound as a chemopreventive agent against cancer.