Neurotoxicity of halogenated phenylacetylureas is linked to abnormal onset of rapid axonal transport.
Neurotoxicity of halogenated phenylacetylureas is linked to abnormal onset of rapid axonal transport.
复制标题
卤化苯乙酰脲的神经毒性与快速轴突运输的异常发生有关。
DOI：
10.1016/0006-8993(86)91554-4
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发表时间：
1986
期刊：
影响因子：
2.9
通讯作者：
Brimijoin,S
中科院分区：
文献类型：
--
作者：
Nagata,H;Brimijoin,S
采用构效关系研究方法，探讨对溴苯基乙酰脲(BPAU)对大鼠神经毒性的作用机制。苯乙酰尿素和7个衍生物在每周两次给药200 mg/kg后，测试了它们引起后肢无力的能力，累积最大剂量为2000 mg/kg。在这项测试中，BPAU和它的氯类似物大致相同，但其他类似物都没有显示出任何神经毒性的证据。由于BPAU的毒性被认为涉及快速轴突运输的异常，因此选定的类似物在运输实验中进行了检验。这些化合物都没有引起最大顺行转运速度的改变，这是在7天前接受400 mg/kg毒物处理的大鼠脊髓内注射[35S]蛋氨酸后测得的。然而，BPAU及其氯类似物都显著缩短了同位素注射和转运开始之间的延迟，这一效果在测试的两个非神经毒性类似物中都看不到。据推测，转运加速是神经病发展的关键步骤，可能会导致细胞器异常，干扰转运颗粒的周转和再循环。
A structure-activity study was performed to investigate the mechanism of neurotoxicity induced in rats by treatment withp-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.