Neurotoxicity of halogenated phenylacetylureas is linked to abnormal onset of rapid axonal transport |
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| Authors: | Hiroshi Nagata Stephen Brimijoin |
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| Affiliation: | 1. School of Agriculture and Food Science, The University of Queensland, Gatton, QLD 4343, Australia;2. Department of Extension and Development, The Malaysian Rubber Board, Kuala Lumpur 50450, Malaysia;3. Department of Rubber Economy and Market, The Malaysian Rubber Board, Kuala Lumpur 50450, Malaysia;1. Laboratory of Aquatic Nutrition and Feed, College of Fisheries, Guangdong Ocean University, Zhanjiang 524088, PR China;2. Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang 524088, PR China;3. Guangdong XIPU Biotechnology Co. Ltd, Guangzhou 510801, PR China;4. Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Animals, Zhanjiang 524088, PR China;1. Shenyang National Laboratory for Materials Science, Institute of Metal Research, Chinese Academy of Sciences, 72 Wenhua Road, Shenyang 110016, China;2. University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China;3. Fraunhofer Institute for Industrial Mathematics, Fraunhofer-Platz 1, Kaiserslautern 67663, Germany;1. Department of Civil Engineering, Central South University, Changsha, China;2. National Engineering Laboratory for Construction Technology of High Speed Rail, Changsha, China;3. Department of Civil Engineering, Monash University, Victoria, Australia |
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| Abstract: | 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. |
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| Keywords: | Motor neurons Rapid axonal transport Experimental neuropathy p-Bromophenylacetylurea Peripheral neurotoxicology |
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