Axonal transport of enzymes and labeled proteins in experimental axonopathy induced by p-bromophenylacetylurea

Summary

Axonal transport was studied by several techniques in the sciatic nerves of adult male Sprague-Dawley rats with neuropathy induced by treatment with p-bromophenylacetylurea (BPAU) in dimethylsulfoxide solution. Control rats were treated with solvent alone. BPAU, 200 mg/kg, induced severe muscle weakness in the hindlimbs, beginning after a latent period of 1 week and progressing to near total paralysis by 2 weeks. Axonal transport of the endogenous transmitter enzymes, acetylcholinesterase, dopamine-β-hydroxylase and choline acetyltransferase, was normal at both 2 and 15 days after administration of BPAU, as judged by the accumulation of enzyme activity above and below a set of double ligatures on the sciatic nerve. The velocity of fast anterograde transport of [³⁵S]methionine labeled protein was also unaffected by BPAU. However, 4 abnormalities of transport were detected in BPAU-treated rats: (1) doubling of the time for initiation of fast anterograde transport after precursor injection in the dorsal root ganglion, (2) 25% fall in the velocity of slow axonal transport of [³H]leucine labeled protein, (3) 30% reduction in the proximal accumulation of fast transported labeled protein in ligated nerve, 8–30 h after injection of precursor, and (4) 50–60% reduction in distal accumulation of ‘early arriving’ labeled protein, 8–14 h after precursor injection. The last abnormality, suggesting an impaired turnaround from anterograde to retrograde transport, was detected as soon as 2 days after BPAU administration. The turnaround abnormality was correlated with the severity of neuropathy as estimated by independent clinical scoring in the group of rats treated with 200 mg/kg of drug. However, further studies showed that turnaround was delayed even in rats treated with doses as low as 50 mg/kg, which never led to clinically evident neuropathy. Nevertheless it is proposed that the abnormalities of transport play a role, as yet undefined, in the distal axonopathy caused by BPAU.