TY - JOUR
T1 - Neurotoxicity of halogenated phenylacetylureas is linked to abnormal onset of rapid axonal transport
AU - Nagata, Hiroshi
AU - Brimijoin, Stephen
N1 - Funding Information:
We are grateful to Dr. Gerald Carlson and Dr. David Kinder for help in synthesizing BPAU and its analogs, to Dr. Matthew Ames for valuable comments on the experimental design, and to Luanne Wussow for the preparation of the charts and manuscript. This work was supported partially by Grant NS 18170 from the National Institute for Neurological and Communicative Disorders and Stroke and by Grant DA 02964 from the National Institute on Drug Abuse. H.N. is the recipient of a postdoctoral fellowship from the Muscular Dystrophy Association of America.
PY - 1986/10/15
Y1 - 1986/10/15
N2 - 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.
AB - 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.
KW - Experimental neuropathy
KW - Motor neurons
KW - Peripheral neurotoxicology
KW - Rapid axonal transport
KW - p-Bromophenylacetylurea
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U2 - 10.1016/0006-8993(86)91554-4
DO - 10.1016/0006-8993(86)91554-4
M3 - Article
C2 - 2429734
AN - SCOPUS:0022484013
SN - 0006-8993
VL - 385
SP - 136
EP - 142
JO - Brain Research
JF - Brain Research
IS - 1
ER -