Neurotoxicity of halogenated phenylacetylureas is linked to abnormal onset of rapid axonal transport.
A structure-activity study was performed to investigate the mechanism of neurotoxicity induced in rats by treatment with p-bromophenylacetylurea (BPAU). Phenylacetylurea and 7 derivatives were tested for their ability to induce hindlimb weakness after twice weekly administration in doses of 200 mg/kg, up to a cumulative maximum of 2000 mg/kg. In this test, BPAU and its chloro- analog were about equipotent, but none of the other analogs displayed any evidence of neurotoxicity. Since BPAU toxicity was believed to involve abnormalities in rapid axonal transport, selected analogs were examined in a transport experiment. None of the compounds led to alterations in the maximal rate of rapid anterograde transport, as measured after intraspinal injections of [35S]methionine in rats treated with 400 mg/kg of toxicant, 7 days earlier. However, both BPAU and its chloro- analog caused marked shortening of the delay between isotope injection and transport onset, an effect not seen with either of the two non-neurotoxic analogs tested. It is hypothesized that the accelerated transport onset is a key step in development of the neuropathy, possibly causing organelle abnormalities that interfere with turnaround and recirculation of transported particles.
D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D005684:Gait / Q000187:drug effects; D008297:Male; D008715:Methionine; D009043:Motor Activity / Q000187:drug effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D051381:Rats; D012584:Sciatic Nerve / Q000502:physiology; D013462:Sulfur Radioisotopes; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D013462:Sulfur Radioisotopes; C004506:4-bromophenylacetylurea; D014508:Urea; D008715:Methionine